Compounds and methods for preventing, treating and/or protecting against sensory hair cell death

ABSTRACT

Disclosed herein are compounds, and pharmaceutical compositions that include such compounds, for preventing, treating, and/or protecting against sensory hair cell death. Methods of using the compounds, alone or in combination with other therapeutic agents, are also disclosed.

CROSS-REFERENCE

The present application is a Continuation of U.S. application Ser. No.14/431,025, filed Mar. 25, 2015, now U.S. Pat. No. 9,416,141, issuedAug. 16, 2016, which is a U.S. National Phase Application under 35U.S.C. § 371 of International Application No. PCT/US2013/062440, filedSep. 27, 2013, which claims the benefit of priority from U.S.provisional application Ser. No. 61/784,410, filed Mar. 14, 2013, andU.S. provisional application Ser. No. 61/707,767, filed Sep. 28, 2012;each of which are incorporated by reference in their entirety.

STATEMENT AS TO FEDERALLY SPONSORED RESEARCH

This invention was made with government support under Grants 5U01NS074506, and 1R01 DC009807 awarded by the National Institutes ofHealth. The government has certain rights in the invention.

BACKGROUND

Aminoglcosides are clinically used drugs that cause dose-dependentsensorineural hearing loss (Smith et al., New Engl J Med, (1977)296:349-53) and are known to kill hair cells in the mammalian inner ear(Theopold, Acta Otolaryngol (1977) 84:57-64). In the U.S. over 2,000,000people receive treatment with aminoglycosides per year. The clinicalefficacy of these drugs in treating resistant bacterial infections andtheir low cost globally account for their continued use and need.Cisplatin, a chemotherapeutic agent is also used for its benefit to lifedespite its toxic effects on the hair cells of the inner ear. Highfrequency hearing loss (>8 kHZ) has been reported to be as high as 90%in children undergoing cisplatin therapy (Allen, et al, Otolaryngol HeadNeck Surg (1998) 118:584-588). The incidence of vestibulotoxic effectsof such drugs on patient populations has been less well studied.Estimates range between 3% and 6% with continued reports in theliterature of patients with aminoglycoside induced vestibulotoxicity(Dhanireddy et al., Arch Otolarngol Head Neck Surg (2005) 131:46-48).Other clinically important and commonly used drugs also have documentedototoxic effects, including loop diuretics (Greenberg, Am J Med Sci,(2000) 319:10-24), antimalarial sesquiterpene lactone endoperoxides(i.e., artemesinins) (Toovey and Jamieson, Trans R Soc Trop Med Hyg(2004) 98:261-7), antimalarial quinines (Claessen, et al., Trop Med IntHealth, (1998) 3:482-9), salicylates (Matz, Ann Otol Rhinol LaryngolSuppl (1990) 148:39-41), and interferon polypeptides (Formann, et al.,Am J Gastroenterol (2004) 99:873-77).

BRIEF SUMMARY OF THE INVENTION

Described herein are compounds of Formula (I), Formula (II), Formula(III), Formula (IV), Formula (V), Formula (VI), or Formula (VII)(hereinafter compounds of Formula (I)-(VII)), pharmaceuticalcompositions comprising said compounds, and methods of use thereof, forpreventing, treating, and/or protecting against sensory hair cell death.In one aspect, compounds of Formula (I)-(VII) prevent sensory hair celldeath. In another aspect, compounds of Formula (I)-(VII) treat sensoryhair cell death. In another aspect, compounds of Formula (I)-(VII)protect against sensory hair cell death.

In another aspect, provided herein is a compound of Formula (I):

wherein:R₁ is C₆-C₁₀aryl or C₃-C₉heteroaryl, wherein C₆-C₁₀aryl andC₃-C₉heteroaryl are optionally substituted with one or more R₄;R₂ is H, C₁-C₄alkyl, or C₂-C₄alkenyl;R₃ is C₂-C₆alkyl, C₂-C₆alkenyl, C₁-C₄haloalkyl, optionally substitutedC₃-C₆cycloalkyl, optionally substituted C₂-C₇heterocycloalkyl,optionally substituted C₆-C₁₀aryl, —OR₆, —NR₅R₆, —C(O)R₇, —CO₂R₆,—C(O)NR₅R₆, —N(R₅)C(O)R₇, —N(R₅)CO₂R₇, —NHS(O)₂R₇, —S(O)₂NR₅R₆,

orR₂ and R₃ together form an optionally substituted C₂-C₇heterocycloalkylring;each R₄ is independently selected from F, Cl, Br, I, —CN, —NO₂, —CF₃,—OR₉, —OCF₃, —NR₈R₉, —C(O)R₁₀, —CO₂R₉, —C(O)NR₈R₉, —N(R₅)C(O)R₁₀,—N(R₅)CO₂R₁₀, —NHS(O)₂R₁₀, —S(O)₂NR₈R₉, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₇heterocycloalkyl, C₆-C₁₀aryl, andC₃-C₉heteroaryl;R₅ is H, or C₁-C₆alkyl;R₆ is H, C₁-C₆alkyl, optionally substituted C₃-C₆cycloalkyl, optionallysubstituted C₂-C₇heterocycloalkyl, optionally substituted C₆-C₁₀aryl,optionally substituted C₃-C₉heteroaryl, optionally substitutedC₁-C₆alkylC₆-C₁₀aryl, or optionally substitutedC₁-C₆alkylC₃-C₉heteroaryl;R₇ is C₁-C₆alkyl, optionally substituted C₃-C₆cycloalkyl, optionallysubstituted C₂-C₇heterocycloalkyl, optionally substituted C₆-C₁₀aryl,C₃-C₉heteroaryl, optionally substituted C₁-C₆alkylC₆-C₁₀aryl, oroptionally substituted C₁-C₆alkylC₃-C₉heteroaryl;R₈ is H, or C₁-C₆alkyl;R₉ is H, C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, C₆-C₁₀aryl,C₃-C₉heteroaryl, C₁-C₆alkylC₆-C₁₀aryl, or C₁-C₆alkylC₃-C₉heteroaryl;R₁₀ is C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, C₆-C₁₀aryl,C₃-C₉heteroaryl, C₁-C₆alkylC₆-C₁₀aryl, or C₁-C₆alkylC₃-C₉heteroaryl;R₁₁ is H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, C₆-C₁₀aryl, C₃-C₉heteroaryl,C₁-C₆alkylC₃-C₆cycloalkyl, C₁-C₆alkylC₆-C₁₀aryl, orC₁-C₆alkylC₃-C₉heteroaryl;R₁₂ is H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, C₆-C₁₀aryl, C₃-C₉heteroaryl,C₁-C₆alkylC₃-C₆cycloalkyl, C₁-C₆alkylC₆-C₁₀aryl, orC₁-C₆alkylC₃-C₉heteroaryl; or R₁₁ and R₁₂ together with the nitrogen towhich they are attached form an optionally substitutedC₂-C₇heterocycloalkyl ring;R₁₃, R₁₄, R₁₅, and R₁₆ are each independently H, or C₁-C₄alkyl;n is an integer selected from 0-4;p is an integer selected from 0-3; andq is an integer selected from 0-3;or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate or hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof.

In another aspect, provided herein is a compound of Formula (II):

wherein:X⁻ is a pharmaceutically acceptable counterion;R₁ is C₆-C₁₀aryl or C₃-C₉heteroaryl, wherein C₆-C₁₀aryl andC₃-C₉heteroaryl are optionally substituted with one or more R₄;R₂ is C₁-C₆alkyl, C₁-C₆alkyl-OR₅, or C₁-C₆alkylC₃-C₆cycloalkyl;R₃ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkyl-OR₅, optionally substitutedC₁-C₆alkylC₃-C₆cycloalkyl, optionally substituted C₂-C₇heterocycloalkyl,C₁-C₆alkyl-CO₂R₆, C₁-C₆alkyl-C(O)NR₅R₆,

orR₂ and R₃ together with the nitrogen to which they are attached form anoptionally substituted C₂-C₇heterocycloalkyl ring;each R₄ is independently selected from F, Cl, Br, I, —CN, —NO₂, —CF₃,—OR₉, —OCF₃, —NR₈R₉, —C(O)R₁₀, —CO₂R₉, —C(O)NR₈R₉, —N(R₈)C(O)R₁₀,—N(R₈)CO₂R₁₀, —NHS(O)₂R₁₀, —S(O)₂NR₈R₉, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₇heterocycloalkyl, C₆-C₁₀aryl, andC₃-C₉heteroaryl;each R₅ is independently H, or C₁-C₆alkyl;R₆ is H, or C₁-C₆alkyl;R₈ is H, or C₁-C₆alkyl;R₉ is H, C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, C₆-C₁₀aryl,C₃-C₉heteroaryl, C₁-C₆alkylC₆-C₁₀aryl, or C₁-C₆alkylC₃-C₉heteroaryl;R₁₀ is C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, C₆-C₁₀aryl,C₃-C₉heteroaryl, C₁-C₆alkylC₆-C₁₀aryl, or C₁-C₆alkylC₃-C₉heteroaryl;R₁₁ is H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, C₆-C₁₀aryl, C₃-C₉heteroaryl,C₁-C₆alkylC₃-C₆cycloalkyl, C₁-C₆alkylC₆-C₁₀aryl, orC₁-C₆alkylC₃-C₉heteroaryl;R₁₂ is H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, C₆-C₁₀aryl, C₃-C₉heteroaryl,C₁-C₆alkylC₃-C₆cycloalkyl, C₁-C₆alkylC₆-C₁₀aryl, orC₁-C₆alkylC₃-C₉heteroaryl;or R₁₁ and R₁₂ together with the nitrogen to which they are attachedform an optionally substituted C₂-C₇heterocycloalkyl ring;R₁₃, R₁₄, R₁₅, and R₁₆ are each independently H, or C₁-C₄alkyl;p is an integer selected from 0-3; andq is an integer selected from 0-3;or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate or hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof.

In another aspect, provided herein is a compound of Formula (III):

wherein:X is a single bond, double bond, —CH₂—, or —O—;R₁ is C₆-C₁₀aryl or C₃-C₉heteroaryl, wherein C₆-C₁₀aryl andC₃-C₉heteroaryl are optionally substituted with one or more R₄;R₂ is H, C₁-C₆alkyl, C₁-C₆alkyl-OR₆, C₁-C₆alkylC₃-C₆cycloalkyl,C₁-C₆alkylC₂-C₇heterocycloalkyl, C₁-C₆alkyl-CO₂R₆, optionallysubstituted C₁-C₆alkylC₆-C₁₀aryl, or optionally substitutedC₁-C₆alkylC₃-C₉heteroaryl;R₃ are R₅ are each independently H, or C₁-C₆alkyl; orR₃ and R₅ together form an optionally substituted C₃-C₆cycloalkyl ring,optionally substituted C₂-C₇heterocycloalkyl ring, optionallysubstituted C₆-C₁₀aryl ring, or an optionally substitutedC₃-C₉heteroaryl ring;each R₄ is independently selected from F, Cl, Br, I, —CN, —NO₂, —CF₃,—OR₉, —OCF₃, —NR₈R₉, —C(O)R₁₀, —CO₂R₉, —C(O)NR₈R₉, —N(R₈)C(O)R₁₀,—N(R₈)CO₂R₁₀, —NHS(O)₂R₁₀, —S(O)₂NR₈R₉, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₇heterocycloalkyl, C₆-C₁₀aryl, andC₃-C₉heteroaryl;R₆ is H, or C₁-C₆alkyl;R₈ is H, or C₁-C₆alkyl;R₉ is H, C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, C₆-C₁₀aryl,C₃-C₉heteroaryl, C₁-C₆alkylC₆-C₁₀aryl, or C₁-C₆alkylC₃-C₉heteroaryl;R₁₀ is C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, C₆-C₁₀aryl,C₃-C₉heteroaryl, C₁-C₆alkylC₆-C₁₀aryl, or C₁-C₆alkylC₃-C₉heteroaryl;R₁₁ is H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, C₆-C₁₀aryl, C₃-C₉heteroaryl,C₁-C₆alkylC₃-C₆cycloalkyl, C₁-C₆alkylC₆-C₁₀aryl, orC₁-C₆alkylC₃-C₉heteroaryl;R₁₂ is H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, C₆-C₁₀aryl, C₃-C₉heteroaryl,C₁-C₆alkylC₃-C₆cycloalkyl, C₁-C₆alkylC₆-C₁₀aryl, orC₁-C₆alkylC₃-C₉heteroaryl;or R₁₁ and R₁₂ together with the nitrogen to which they are attachedform an optionally substituted C₂-C₇heterocycloalkyl ring; andR₁₃ are R₁₄ are each independently H, or C₁-C₆alkyl;or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate or hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof.

In another aspect, provided herein is a compound of Formula (IV):

wherein:R₁ is C₆-C₁₀aryl or C₃-C₉heteroaryl, wherein C₆-C₁₀aryl andC₃-C₉heteroaryl are optionally substituted with one or more R₄;R₂ is H, —CH₃, —CH₂CH₃, or —CH(CH₃)₂;each R₄ is independently selected from F, Br, I, —CN, —NO₂, —OR₉, —OCF₃,—NR₈R₉, —C(O)NR₈R₉, —N(R₈)C(O)R₁₀, —N(R₈)CO₂R₁₀, —NHS(O)₂R₁₀,—S(O)₂NR₈R₉, C₂-C₆alkyl, C₃-C₆cycloalkyl, C₁-C₆heteroalkyl,C₂-C₇heterocycloalkyl, C₆-C₁₀aryl, and C₃-C₉heteroaryl;R₈ is H, or C₁-C₆alkyl;R₉ is H, C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, C₆-C₁₀aryl,C₃-C₉heteroaryl, C₁-C₆alkylC₆-C₁₀aryl, or C₁-C₆alkylC₃-C₉heteroaryl;R₁₀ is C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, C₆-C₁₀aryl,C₃-C₉heteroaryl, C₁-C₆alkylC₆-C₁₀aryl, or C₁-C₆alkylC₃-C₉heteroaryl;R₁₁ is H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, C₆-C₁₀aryl, C₃-C₉heteroaryl,C₁-C₆alkylC₃-C₆cycloalkyl, C₁-C₆alkylC₆-C₁₀aryl, orC₁-C₆alkylC₃-C₉heteroaryl;R₁₂ is H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, C₆-C₁₀aryl, C₃-C₉heteroaryl,C₁-C₆alkylC₃-C₆cycloalkyl, C₁-C₆alkylC₆-C₁₀aryl, orC₁-C₆alkylC₃-C₉heteroaryl;or R₁₁ and R₁₂ together with the nitrogen to which they are attachedform an optionally substituted C₂-C₇heterocycloalkyl ring;p is an integer selected from 0-3; andq is an integer selected from 0-3;or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, or pharmaceutically acceptable prodrug thereof.

In another aspect, provided herein is a compound of Formula (V):

wherein:R₁ is C₆-C₁₀aryl or C₃-C₉heteroaryl, wherein C₆-C₁₀aryl andC₃-C₉heteroaryl are optionally substituted with one or more R₄;each R₂ is independently H, or C₁-C₄alkyl;R₃ is H, C₁-C₆alkyl, C₁-C₆haloalkyl, optionally substitutedC₃-C₆cycloalkyl, optionally substituted C₂-C₇heterocycloalkyl,optionally substituted C₆-C₁₀aryl, optionally substitutedC₃-C₉heteroaryl, —OR₆, —NR₅R₆, —C(O)R₇, —CO₂R₆, —C(O)NR₅R₆,—N(R₅)C(O)R₇, —N(R₅)CO₂R₇, —NHS(O)₂R₇, —S(O)₂NR₅R₆,

orR₂ and R₃ together form an optionally substituted C₂-C₇heterocycloalkylring;each R₄ is independently selected from F, Cl, Br, I, —CN, —NO₂, —CF₃,—OR₉, —OCF₃, —NR₈R₉, —C(O)R₁₀, —CO₂R₉, —C(O)NR₈R₉, —N(R₈)C(O)R₁₀,—N(R₈)CO₂R₁₀, —NHS(O)₂R₁₀, —S(O)₂NR₈R₉, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₇heterocycloalkyl, C₆-C₁₀aryl, andC₃-C₉heteroaryl;R₅ is H, or C₁-C₆alkyl;R₆ is H, C₁-C₆alkyl, optionally substituted C₃-C₆cycloalkyl, optionallysubstituted C₂-C₇heterocycloalkyl, optionally substituted C₆-C₁₀aryl,optionally substituted C₃-C₉heteroaryl, optionally substitutedC₁-C₆alkylC₆-C₁₀aryl, or optionally substitutedC₁-C₆alkylC₃-C₉heteroaryl;R₇ is C₁-C₆alkyl, optionally substituted C₃-C₆cycloalkyl, optionallysubstituted C₂-C₇heterocycloalkyl, optionally substituted C₆-C₁₀aryl,C₃-C₉heteroaryl, optionally substituted C₁-C₆alkylC₆-C₁₀aryl, oroptionally substituted C₁-C₆alkylC₃-C₉heteroaryl;R₈ is H, or C₁-C₆alkyl;R₉ is H, C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, C₆-C₁₀aryl,C₃-C₉heteroaryl, C₁-C₆alkylC₆-C₁₀aryl, or C₁-C₆alkylC₃-C₉heteroaryl;R₁₀ is C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, C₆-C₁₀aryl,C₃-C₉heteroaryl, C₁-C₆alkylC₆-C₁₀aryl, or C₁-C₆alkylC₃-C₉heteroaryl;R₁₁ is H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, C₆-C₁₀aryl, C₃-C₉heteroaryl,C₁-C₆alkylC₃-C₆cycloalkyl, C₁-C₆alkylC₆-C₁₀aryl, orC₁-C₆alkylC₃-C₉heteroaryl;R₁₂ is H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, C₆-C₁₀aryl, C₃-C₉heteroaryl,C₁-C₆alkylC₃-C₆cycloalkyl, C₁-C₆alkylC₆-C₁₀aryl, orC₁-C₆alkylC₃-C₉heteroaryl;or R₁₁ and R₁₂ together with the nitrogen to which they are attachedform an optionally substituted C₂-C₇heterocycloalkyl ring;R₁₃, R₁₄, R₁₅, and R₁₆ are each independently H, or C₁-C₄alkyl, whereinat least one of R₁₃, R₁₄, R₁₅, and R₁₆ is not H; or R₃ and R₁₃ togetherform an optionally substituted C₂-C₇heterocycloalkyl ring; or R₃ and R₁₅together form an optionally substituted C₂-C₇heterocycloalkyl ring; andn is an integer selected from 0-5;p is an integer selected from 0-3; andq is an integer selected from 0-3;or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate or hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof.

In another aspect, provided herein is a compound of Formula (VI):

wherein:X is a single bond, double bond, —CH₂—, or —O—;R₁ is C₆-C₁₀aryl or C₃-C₉heteroaryl, wherein C₆-C₁₀aryl andC₃-C₉heteroaryl are optionally substituted with one or more R₄;R_(2a) is C₁-C₆alkyl, C₁-C₆alkyl-OR₅, or C₁-C₆alkylC₃-C₆cycloalkyl;R₂ is C₁-C₆alkyl, C₁-C₆alkyl-OR₆, C₁-C₆alkylC₃-C₆cycloalkyl, orC₁-C₆alkyl-CO₂R₆;R₃ are R₅ are each independently H, or C₁-C₆alkyl; orR₃ and R₅ together form an optionally substituted C₃-C₆cycloalkyl ring,optionally substituted C₂-C₇heterocycloalkyl ring, optionallysubstituted C₆-C₁₀aryl ring, or an optionally substitutedC₃-C₉heteroaryl ring;each R₄ is independently selected from F, Cl, Br, I, —CN, —NO₂, —CF₃,—OR₉, —OCF₃, —NR₈R₉, —C(O)R₁₀, —CO₂R₉, —C(O)NR₈R₉, —N(R₈)C(O)R₁₀,—N(R₈)CO₂R₁₀, —NHS(O)₂R₁₀, —S(O)₂NR₈R₉, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₇heterocycloalkyl, C₆-C₁₀aryl, andC₃-C₉heteroaryl;R₆ is H, or C₁-C₆alkyl;R₈ is H, or C₁-C₆alkyl;R₉ is H, C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, C₆-C₁₀aryl,C₃-C₉heteroaryl, C₁-C₆alkylC₆-C₁₀aryl, or C₁-C₆alkylC₃-C₉heteroaryl;R₁₀ is C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, C₆-C₁₀aryl,C₃-C₉heteroaryl, C₁-C₆alkylC₆-C₁₀aryl, or C₁-C₆alkylC₃-C₉heteroaryl;R₁₁ is H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, C₆-C₁₀aryl, C₃-C₉heteroaryl,C₁-C₆alkylC₃-C₆cycloalkyl, C₁-C₆alkylC₆-C₁₀aryl, orC₁-C₆alkylC₃-C₉heteroaryl;R₁₂ is H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, C₆-C₁₀aryl, C₃-C₉heteroaryl,C₁-C₆alkylC₃-C₆cycloalkyl, C₁-C₆alkylC₆-C₁₀aryl, orC₁-C₆alkylC₃-C₉heteroaryl;or R₁₁ and R₁₂ together with the nitrogen to which they are attachedform an optionally substituted C₂-C₇heterocycloalkyl ring; andR₁₃ are R₁₄ are each independently H, or C₁-C₆alkyl;or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate or hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof.

In another aspect, provided herein is a compound of Formula (VII):

wherein:R₁ is C₆-C₁₀aryl or C₃-C₉heteroaryl, wherein C₆-C₁₀aryl andC₃-C₉heteroaryl are optionally substituted with one or more R₄;R₂ is H, C₁-C₆alkyl, C₁-C₆alkyl-NR₅R₆, C₁-C₆alkyl-OR₅, orC₁-C₆alkylC₃-C₆cycloalkyl;R₃ is —NR₅R₆, C₁-C₆alkyl-NR₅R₆, C₁-C₆haloalkyl, C₁-C₆alkyl-OR₅,optionally substituted C₁-C₆alkylC₃-C₆cycloalkyl, optionally substitutedC₂-C₇heterocycloalkyl, C₁-C₆alkyl-CO₂R₆, C₁-C₆alkyl-C(O)NR₅R₆,

orR₂ and R₃ together with the carbon atom to which they are attached forman optionally substituted C₂-C₇heterocycloalkyl ring;each R₄ is independently selected from F, Cl, Br, I, —CN, —NO₂, —CF₃,—OR₉, —OCF₃, —NR₈R₉, —C(O)R₁₀, —CO₂R₉, —C(O)NR₈R₉, —N(R₈)C(O)R₁₀,—N(R₈)CO₂R₁₀, —NHS(O)₂R₁₀, —S(O)₂NR₈R₉, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₇heterocycloalkyl, C₆-C₁₀aryl, andC₃-C₉heteroaryl;each R₅ is independently H, or C₁-C₆alkyl;R₆ is H, or C₁-C₆alkyl;R₈ is H, or C₁-C₆alkyl;R₉ is H, C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, C₆-C₁₀aryl,C₃-C₉heteroaryl, C₁-C₆alkylC₆-C₁₀aryl, or C₁-C₆alkylC₃-C₉heteroaryl;R₁₀ is C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, C₆-C₁₀aryl,C₃-C₉heteroaryl, C₁-C₆alkylC₆-C₁₀aryl, or C₁-C₆alkylC₃-C₉heteroaryl;R₁₁ is H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, C₆-C₁₀aryl, C₃-C₉heteroaryl,C₁-C₆alkylC₃-C₆cycloalkyl, C₁-C₆alkylC₆-C₁₀aryl, orC₁-C₆alkylC₃-C₉heteroaryl;R₁₂ is H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, C₆-C₁₀aryl, C₃-C₉heteroaryl,C₁-C₆alkylC₃-C₆cycloalkyl, C₁-C₆alkylC₆-C₁₀aryl, orC₁-C₆alkylC₃-C₉heteroaryl;or R₁₁ and R₁₂ together with the nitrogen to which they are attachedform an optionally substituted C₂-C₇heterocycloalkyl ring;R₁₃, R₁₄, R₁₅, and R₁₆ are each independently H, or C₁-C₄alkyl;p is an integer selected from 0-3; andq is an integer selected from 0-3;or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate or hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof.

In another aspect is a pharmaceutical composition comprising a compoundof Formula (I)-(VII) and a pharmaceutically acceptable excipient. Inanother embodiment is a pharmaceutical composition comprising a compoundof Formula (I)-(VII) and a pharmaceutically acceptable excipient furthercomprising an aminoglycoside antibiotic. In another embodiment is apharmaceutical composition comprising a compound of Formula (I)-(VII)and a pharmaceutically acceptable excipient further comprising anaminoglycoside antibiotic wherein the aminoglycoside antibiotic isselected from streptomycin, neomycin, framycetin, paromomycin,paromomycin sulfate, ribostamycin, kanamycin, amikacin, arbekacin,bekanamycin, dibekacin, tobramycin, spectinomycin, hygromycin B,gentamicin, netilmicin, sisomicin, isepamicin, verdamicin, andastromicin. In some embodiments is a pharmaceutical compositioncomprising a compound of Formula (I)-(VII) and a pharmaceuticallyacceptable excipient further comprising an aminoglycoside antibioticwherein the aminoglycoside antibiotic is streptomycin. In someembodiments is a pharmaceutical composition comprising a compound ofFormula (I)-(VII) and a pharmaceutically acceptable excipient furthercomprising an aminoglycoside antibiotic wherein the aminoglycosideantibiotic is neomycin. In some embodiments is a pharmaceuticalcomposition comprising a compound of Formula (I)-(VII) and apharmaceutically acceptable excipient further comprising anaminoglycoside antibiotic wherein the aminoglycoside antibiotic isamikacin. In some embodiments is a pharmaceutical composition comprisinga compound of Formula (I)-(VII) and a pharmaceutically acceptableexcipient further comprising an aminoglycoside antibiotic wherein theaminoglycoside antibiotic is gentamicin. In some embodiments is apharmaceutical composition comprising a compound of Formula (I)-(VII)and a pharmaceutically acceptable excipient further comprising anaminoglycoside antibiotic wherein the aminoglycoside antibiotic iskanamycin. In some embodiments is a pharmaceutical compositioncomprising a compound of Formula (I)-(VII) and a pharmaceuticallyacceptable excipient further comprising an aminoglycoside antibioticwherein the aminoglycoside antibiotic is tobramycin. In anotherembodiment of the aforementioned embodiments is a pharmaceuticalcomposition formulated for intravenous, intramuscular, or subcutaneousadministration.

In another aspect is a method for preventing, treating, and/orprotecting against sensory hair cell death in an individual comprisingadministering to the individual a therapeutically effective amount of acompound of Formula (I)-(VII). In another embodiment is a method forpreventing, treating, and/or protecting against sensory hair cell deathin an individual comprising administering to the individual atherapeutically effective amount of a compound of Formula (I)-(VII)wherein the sensory hair cell death is associated with exposure to anototoxic agent. In another embodiment is a method for preventing,treating, and/or protecting against sensory hair cell death in anindividual comprising administering to the individual a therapeuticallyeffective amount of a compound of Formula (I)-(VII) wherein the sensoryhair cell death is associated with exposure to an ototoxic agent and theototoxic agent is an aminoglycoside antibiotic, chemotherapeutic agent,loop diuretic, antimalarial sesquiterpene lactone endoperoxide,antimalarial quinine, salicylate, or interferon polypeptide. In anotherembodiment is a method for preventing, treating, and/or protectingagainst sensory hair cell death in an individual comprisingadministering to the individual a therapeutically effective amount of acompound of Formula (I)-(VII) wherein the sensory hair cell death isassociated with exposure to an aminoglycoside antibiotic. In anotherembodiment is a method for preventing, treating, and/or protectingagainst sensory hair cell death in an individual comprisingadministering to the individual a therapeutically effective amount of acompound of Formula (I)-(VII) wherein the sensory hair cell death isassociated with exposure to an aminoglycoside antibiotic and theaminoglycoside antibiotic is selected from streptomycin, neomycin,framycetin, paromomycin, paromomycin sulfate, ribostamycin, kanamycin,amikacin, arbekacin, bekanamycin, dibekacin, tobramycin, spectinomycin,hygromycin B, gentamicin, netilmicin, sisomicin, isepamicin, verdamicin,and astromicin. In another embodiment is a method for preventing,treating, and/or protecting against sensory hair cell death in anindividual comprising administering to the individual a therapeuticallyeffective amount of a compound of Formula (I)-(VII) wherein the sensoryhair cell death is associated with exposure to streptomycin. In anotherembodiment is a method for preventing, treating, and/or protectingagainst sensory hair cell death in an individual comprisingadministering to the individual a therapeutically effective amount of acompound of Formula (I)-(VII) wherein the sensory hair cell death isassociated with exposure to neomycin. In another embodiment is a methodfor preventing, treating, and/or protecting against sensory hair celldeath in an individual comprising administering to the individual atherapeutically effective amount of a compound of Formula (I)-(VII)wherein the sensory hair cell death is associated with exposure toamikacin. In another embodiment is a method for preventing, treating,and/or protecting against sensory hair cell death in an individualcomprising administering to the individual a therapeutically effectiveamount of a compound of Formula (I)-(VII) wherein the sensory hair celldeath is associated with exposure to gentamicin. In another embodimentis a method for preventing, treating, and/or protecting against sensoryhair cell death in an individual comprising administering to theindividual a therapeutically effective amount of a compound of Formula(I)-(VII) wherein the sensory hair cell death is associated withexposure to kanamycin. In another embodiment is a method for preventing,treating, and/or protecting against sensory hair cell death in anindividual comprising administering to the individual a therapeuticallyeffective amount of a compound of Formula (I)-(VII) wherein the sensoryhair cell death is associated with exposure to tobramycin. In anotherembodiment is a method for preventing, treating, and/or protectingagainst sensory hair cell death in an individual comprisingadministering to the individual a therapeutically effective amount of acompound of Formula (I)-(VII) wherein the sensory hair cell death isassociated with exposure to a chemotherapeutic agent. In anotherembodiment is a method for preventing, treating, and/or protectingagainst sensory hair cell death in an individual comprisingadministering to the individual a therapeutically effective amount of acompound of Formula (I)-(VII) wherein the sensory hair cell death isassociated with exposure to a chemotherapeutic agent and thechemotherapeutic agent is selected from cisplatin or carboplatin.

In another aspect is a compound with a maximum hair cell protection ofgreater than 50% in the assay described in Example 231.

In another aspect is the use of the assay described in Example 231 forthe testing of a compound of Formula (I)-(VII).

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows hair cell survival in the zebrafish assay followingtreatment with neomycin and PROTO-1.

FIG. 2 shows hair cell survival in the zebrafish assay followingtreatment with amikacin and PROTO-1.

FIG. 3 shows hair cell survival in the zebrafish assay followingtreatment with streptomycin and PROTO-1.

FIG. 4 shows hair cell survival in the zebrafish assay followingtreatment with gentamicin and PROTO-1.

FIG. 5 shows hair cell survival in the zebrafish assay followingtreatment with kanamycin and PROTO-1.

DETAILED DESCRIPTION OF THE INVENTION

As used herein and in the appended claims, the singular forms “a,”“and,” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “an agent” includesa plurality of such agents, and reference to “the cell” includesreference to one or more cells (or to a plurality of cells) andequivalents thereof. When ranges are used herein for physicalproperties, such as molecular weight, or chemical properties, such aschemical formulae, all combinations and subcombinations of ranges andspecific embodiments therein are intended to be included. The term“about” when referring to a number or a numerical range means that thenumber or numerical range referred to is an approximation withinexperimental variability (or within statistical experimental error), andthus the number or numerical range may vary between 1% and 15% of thestated number or numerical range. The term “comprising” (and relatedterms such as “comprise” or “comprises” or “having” or “including”) isnot intended to exclude that in other certain embodiments, for example,an embodiment of any composition of matter, composition, method, orprocess, or the like, described herein, may “consist of” or “consistessentially of” the described features.

Definitions

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated below.

“Amino” refers to the —NH₂ radical.

“Cyano” refers to the —CN radical.

“Nitro” refers to the —NO₂ radical.

“Oxa” refers to the —O— radical.

“Oxo” refers to the ═O radical.

“Thioxo” refers to the ═S radical.

“Imino” refers to the ═N—H radical.

“Oximo” refers to the ═N—OH radical.

“Hydrazino” refers to the ═N—NH₂ radical.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to fifteen carbon atoms (e.g., C₁-C₁₅alkyl). In certain embodiments, an alkyl comprises one to thirteencarbon atoms (e.g., C₁-C₁₃ alkyl). In certain embodiments, an alkylcomprises one to eight carbon atoms (e.g., C₁-C₈ alkyl). In otherembodiments, an alkyl comprises one to six carbon atoms (e.g., C₁-C₆alkyl). In other embodiments, an alkyl comprises one to five carbonatoms (e.g., C₁-C₅ alkyl). In other embodiments, an alkyl comprises oneto four carbon atoms (e.g., C₁-C₄ alkyl). In other embodiments, an alkylcomprises one to three carbon atoms (e.g., C₁-C₃ alkyl). In otherembodiments, an alkyl comprises one to two carbon atoms (e.g., C₁-C₂alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g.,C₁ alkyl). In other embodiments, an alkyl comprises five to fifteencarbon atoms (e.g., C₅-C₁₅ alkyl). In other embodiments, an alkylcomprises five to eight carbon atoms (e.g., C₅-C₈ alkyl). In otherembodiments, an alkyl comprises two to six carbon atoms (e.g., C₂-C₆alkyl). In other embodiments, an alkyl comprises two to five carbonatoms (e.g., C₂-C₅ alkyl). In other embodiments, an alkyl comprisesthree to five carbon atoms (e.g., C₃-C₈ alkyl). In other embodiments,the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl),1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl(sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl),1-pentyl (n-pentyl). Unless stated otherwise specifically in thespecification, an alkyl group is optionally substituted by one or moreof the following substituents: halo, cyano, nitro, oxo, thioxo, imino,oximo, trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is1 or 2) and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl orheteroarylalkyl. Depending on the structure, an alkyl group isoptionally a monoradical or a diradical (i.e. an alkylene group).

“Alkoxy” refers to a radical bonded through an oxygen atom of theformula —O-alkyl, where alkyl is an alkyl chain as defined above.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon double bond, and having from two to twelvecarbon atoms. In certain embodiments, an alkenyl comprises two to eightcarbon atoms. In other embodiments, an alkenyl comprises two to sixcarbon atoms. In other embodiments, an alkenyl comprises two to fourcarbon atoms. The alkenyl is attached to the rest of the molecule by asingle bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e.,allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unlessstated otherwise specifically in the specification, an alkenyl group isoptionally substituted by one or more of the following substituents:halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl,—OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂,—N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2)and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl orheteroarylalkyl.

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon triple bond, having from two to twelve carbonatoms. In certain embodiments, an alkynyl comprises two to eight carbonatoms. In other embodiments, an alkynyl has two to four carbon atoms.The alkynyl is attached to the rest of the molecule by a single bond,for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and thelike. Unless stated otherwise specifically in the specification, analkynyl group is optionally substituted by one or more of the followingsubstituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is1 or 2) and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl orheteroarylalkyl.

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking the rest of the molecule to a radical group,consisting solely of carbon and hydrogen, containing no unsaturation andhaving from one to twelve carbon atoms, for example, methylene,ethylene, propylene, n-butylene, and the like. The alkylene chain isattached to the rest of the molecule through a single bond and to theradical group through a single bond. The points of attachment of thealkylene chain to the rest of the molecule and to the radical group isoptionally through one carbon in the alkylene chain or through any twocarbons within the chain. In certain embodiments, an alkylene comprisesone to eight carbon atoms (e.g., C₁-C₈alkylene). In other embodiments,an alkylene comprises one to five carbon atoms (e.g., C₁-C₅alkylene). Inother embodiments, an alkylene comprises one to four carbon atoms (e.g.,C₁-C₄alkylene). In other embodiments, an alkylene comprises one to threecarbon atoms (e.g., C₁-C₃alkylene). In other embodiments, an alkylenecomprises one to two carbon atoms (e.g., C₁-C₂alkylene). In otherembodiments, an alkylene comprises one carbon atom (e.g., C₁ alkylene).In other embodiments, an alkylene comprises five to eight carbon atoms(e.g., C₅-C₈ alkylene). In other embodiments, an alkylene comprises twoto five carbon atoms (e.g., C₂-C₅ alkylene). In other embodiments, analkylene comprises three to five carbon atoms (e.g., C₃-C₅ alkylene).Unless stated otherwise specifically in the specification, an alkylenechain is optionally substituted by one or more of the followingsubstituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is1 or 2) and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl orheteroarylalkyl.

“Aryl” refers to a radical derived from an aromatic monocyclic ormulticyclic hydrocarbon ring system by removing a hydrogen atom from aring carbon atom. The aromatic monocyclic or multicyclic hydrocarbonring system contains only hydrogen and carbon from five to eighteencarbon atoms, where at least one of the rings in the ring system isfully unsaturated, i.e., it contains a cyclic, delocalized (4n+2)π-electron system in accordance with the Hückel theory. The ring systemfrom which aryl groups are derived include, but are not limited to,groups such as benzene, fluorene, indane, indene, tetralin andnaphthalene. Unless stated otherwise specifically in the specification,the term “aryl” or the prefix “ar-” (such as in “aralkyl”) is meant toinclude aryl radicals optionally substituted by one or more substituentsindependently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,cyano, nitro, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substitutedaralkynyl, optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocycloalkyl, optionallysubstituted heterocycloalkylalkyl, optionally substituted heteroaryl,optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl (optionally substituted with one or more halo groups), aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl,each R^(b) is independently a direct bond or a straight or branchedalkylene or alkenylene chain, and R^(c) is a straight or branchedalkylene or alkenylene chain, and where each of the above substituentsis unsubstituted unless otherwise indicated.

“Aralkyl” refers to a radical of the formula —R^(c)-aryl where R^(c) isan alkylene chain as defined above, for example, methylene, ethylene,and the like. The alkylene chain part of the aralkyl radical isoptionally substituted as described above for an alkylene chain. Thearyl part of the aralkyl radical is optionally substituted as describedabove for an aryl group.

“Aralkenyl” refers to a radical of the formula —R^(d)-aryl where R^(d)is an alkenylene chain as defined above. The aryl part of the aralkenylradical is optionally substituted as described above for an aryl group.The alkenylene chain part of the aralkenyl radical is optionallysubstituted as defined above for an alkenylene group.

“Aralkynyl” refers to a radical of the formula —R^(e)-aryl, where R^(e)is an alkynylene chain as defined above. The aryl part of the aralkynylradical is optionally substituted as described above for an aryl group.The alkynylene chain part of the aralkynyl radical is optionallysubstituted as defined above for an alkynylene chain.

“Aralkoxy” refers to a radical bonded through an oxygen atom of theformula —O—R^(c)-aryl where R^(c) is an alkylene chain as defined above,for example, methylene, ethylene, and the like. The alkylene chain partof the aralkyl radical is optionally substituted as described above foran alkylene chain. The aryl part of the aralkyl radical is optionallysubstituted as described above for an aryl group.

“Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,which may include fused or bridged ring systems, having from three tofifteen carbon atoms. In certain embodiments, a cycloalkyl comprisesthree to ten carbon atoms. In other embodiments, a cycloalkyl comprisesfive to seven carbon atoms. The cycloalkyl is attached to the rest ofthe molecule by a single bond. Cycloalkyl may be saturated, (i.e.,containing single C—C bonds only) or partially unsaturated. Examples ofmonocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturatedcycloalkyl is also referred to as “cycloalkenyl.” Examples of monocycliccycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl,and cyclooctenyl. Polycyclic cycloalkyl radicals include, for example,adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl,decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unlessotherwise stated specifically in the specification, the term“cycloalkyl” is meant to include cycloalkyl radicals that are optionallysubstituted by one or more substituents independently selected fromalkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted aralkenyl, optionally substituted aralkynyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted heterocycloalkyl, optionally substitutedheterocycloalkylalkyl, optionally substituted heteroaryl, optionallysubstituted heteroarylalkyl, —R^(b)—OR^(a), —R^(b)—OC(O)—R^(a),—R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂,—R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂,—R^(b)—O—R—C(O)N(R^(a))₂, —R^(b)—N(R^(a))C(O)OR^(a),—R^(b)—N(R^(a))C(O)R^(a), —R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2) and —R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2),where each R^(a) is independently hydrogen, alkyl, fluoroalkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, each R^(b) isindependently a direct bond or a straight or branched alkylene oralkenylene chain, and R^(c) is a straight or branched alkylene oralkenylene chain, and where each of the above substituents isunsubstituted unless otherwise indicated.

“Cycloalkylalkyl” refers to a radical of the formula —R^(c)-cycloalkylwhere R^(c) is an alkylene chain as defined above. The alkylene chainand the cycloalkyl radical is optionally substituted as defined above.

“Cycloalkylalkoxy” refers to a radical bonded through an oxygen atom ofthe formula —O—R^(c)-cycloalkyl where R^(c) is an alkylene chain asdefined above. The alkylene chain and the cycloalkyl radical isoptionally substituted as defined above.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodosubstituents.

“Fluoroalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more fluoro radicals, as defined above, forexample, trifluoromethyl, difluoromethyl, fluoromethyl,2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. Thealkyl part of the fluoroalkyl radical may be optionally substituted asdefined above for an alkyl group.

“Heterocycloalkyl” refers to a stable 3- to 18-membered non-aromaticring radical that comprises two to twelve carbon atoms and from one tosix heteroatoms selected from nitrogen, oxygen and sulfur. Unless statedotherwise specifically in the specification, the heterocycloalkylradical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system,which may include fused or bridged ring systems. The heteroatoms in theheterocycloalkyl radical may be optionally oxidized. One or morenitrogen atoms, if present, are optionally quaternized. Theheterocycloalkyl radical is partially or fully saturated. Theheterocycloalkyl may be attached to the rest of the molecule through anyatom of the ring(s). Examples of such heterocycloalkyl radicals include,but are not limited to, dioxolanyl, thienyl[1,3]dithianyl,decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl,isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl,piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl,quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl,tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl,1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless statedotherwise specifically in the specification, the term “heterocycloalkyl”is meant to include heterocycloalkyl radicals as defined above that areoptionally substituted by one or more substituents selected from alkyl,alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted aralkenyl, optionally substituted aralkynyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted heterocycloalkyl, optionally substitutedheterocycloalkylalkyl, optionally substituted heteroaryl, optionallysubstituted heteroarylalkyl, —R^(b)—OR^(a), —R^(b)—OC(O)—R^(a),—R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂,—R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂,—R^(b)—O—R^(c)—C(O)N(R^(a))₂, —R^(b)—N(R^(a))C(O)OR^(a),—R^(b)—N(R^(a))C(O)R^(a), —R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2) and —R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2),where each R^(a) is independently hydrogen, alkyl, fluoroalkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, each R^(b) isindependently a direct bond or a straight or branched alkylene oralkenylene chain, and R^(c) is a straight or branched alkylene oralkenylene chain, and where each of the above substituents isunsubstituted unless otherwise indicated.

“N-heterocycloalkyl” or “N-attached heterocycloalkyl” refers to aheterocycloalkyl radical as defined above containing at least onenitrogen and where the point of attachment of the heterocycloalkylradical to the rest of the molecule is through a nitrogen atom in theheterocycloalkyl radical. An N-heterocycloalkyl radical is optionallysubstituted as described above for heterocycloalkyl radicals. Examplesof such N-heterocycloalkyl radicals include, but are not limited to,1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl,pyrazolidinyl, imidazolinyl, and imidazolidinyl.

“C-heterocycloalkyl” or “C-attached heterocycloalkyl” refers to aheterocycloalkyl radical as defined above containing at least oneheteroatom and where the point of attachment of the heterocycloalkylradical to the rest of the molecule is through a carbon atom in theheterocycloalkyl radical. A C-heterocycloalkyl radical is optionallysubstituted as described above for heterocycloalkyl radicals. Examplesof such C-heterocycloalkyl radicals include, but are not limited to,2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or3-pyrrolidinyl, and the like.

“Heterocycloalkylalkyl” refers to a radical of the formula—R^(c)-heterocycloalkyl where R^(c) is an alkylene chain as definedabove. If the heterocycloalkyl is a nitrogen-containingheterocycloalkyl, the heterocycloalkyl is optionally attached to thealkyl radical at the nitrogen atom. The alkylene chain of theheterocycloalkylalkyl radical is optionally substituted as defined abovefor an alkylene chain. The heterocycloalkyl part of theheterocycloalkylalkyl radical is optionally substituted as defined abovefor a heterocycloalkyl group.

“Heterocycloalkylalkoxy” refers to a radical bonded through an oxygenatom of the formula —O—R^(c)-heterocycloalkyl where R^(c) is an alkylenechain as defined above. If the heterocycloalkyl is a nitrogen-containingheterocycloalkyl, the heterocycloalkyl is optionally attached to thealkyl radical at the nitrogen atom. The alkylene chain of theheterocycloalkylalkoxy radical is optionally substituted as definedabove for an alkylene chain. The heterocycloalkyl part of theheterocycloalkylalkoxy radical is optionally substituted as definedabove for a heterocycloalkyl group.

“Heteroaryl” refers to a radical derived from a 3- to 18-memberedaromatic ring radical that comprises two to seventeen carbon atoms andfrom one to six heteroatoms selected from nitrogen, oxygen and sulfur.As used herein, the heteroaryl radical may be a monocyclic, bicyclic,tricyclic or tetracyclic ring system, wherein at least one of the ringsin the ring system is fully unsaturated, i.e., it contains a cyclic,delocalized (4n+2) π-electron system in accordance with the Hückeltheory. Heteroaryl includes fused or bridged ring systems. Theheteroatom(s) in the heteroaryl radical is optionally oxidized. One ormore nitrogen atoms, if present, are optionally quaternized. Theheteroaryl is attached to the rest of the molecule through any atom ofthe ring(s). Examples of heteroaryls include, but are not limited to,azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl,benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl,pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl,pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl,quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e.thienyl). Unless stated otherwise specifically in the specification, theterm “heteroaryl” is meant to include heteroaryl radicals as definedabove which are optionally substituted by one or more substituentsselected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl,haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl,optionally substituted aralkyl, optionally substituted aralkenyl,optionally substituted aralkynyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocycloalkyl, optionally substituted heterocycloalkylalkyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, —R^(b)—OR^(a), —R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a),—R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a),—R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl orheteroarylalkyl, each R^(b) is independently a direct bond or a straightor branched alkylene or alkenylene chain, and R^(c) is a straight orbranched alkylene or alkenylene chain, and where each of the abovesubstituents is unsubstituted unless otherwise indicated.

“N-heteroaryl” refers to a heteroaryl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heteroaryl radical to the rest of the molecule is through a nitrogenatom in the heteroaryl radical. An N-heteroaryl radical is optionallysubstituted as described above for heteroaryl radicals.

“C-heteroaryl” refers to a heteroaryl radical as defined above and wherethe point of attachment of the heteroaryl radical to the rest of themolecule is through a carbon atom in the heteroaryl radical. AC-heteroaryl radical is optionally substituted as described above forheteroaryl radicals.

“Heteroarylalkyl” refers to a radical of the formula —R^(c)-heteroaryl,where R^(c) is an alkylene chain as defined above. If the heteroaryl isa nitrogen-containing heteroaryl, the heteroaryl is optionally attachedto the alkyl radical at the nitrogen atom. The alkylene chain of theheteroarylalkyl radical is optionally substituted as defined above foran alkylene chain. The heteroaryl part of the heteroarylalkyl radical isoptionally substituted as defined above for a heteroaryl group.

“Heteroarylalkoxy” refers to a radical bonded through an oxygen atom ofthe formula —O—R^(c)-heteroaryl, where R^(c) is an alkylene chain asdefined above. If the heteroaryl is a nitrogen-containing heteroaryl,the heteroaryl is optionally attached to the alkyl radical at thenitrogen atom. The alkylene chain of the heteroarylalkoxy radical isoptionally substituted as defined above for an alkylene chain. Theheteroaryl part of the heteroarylalkoxy radical is optionallysubstituted as defined above for a heteroaryl group.

The compounds disclosed herein may contain one or more asymmetriccenters and may thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)-. Unless stated otherwise, it isintended that all stereoisomeric forms of the compounds disclosed hereinare contemplated by this disclosure. When the compounds described hereincontain alkene double bonds, and unless specified otherwise, it isintended that this disclosure includes both E and Z geometric isomers(e.g., cis or trans.) Likewise, all possible isomers, as well as theirracemic and optically pure forms, and all tautomeric forms are alsointended to be included. The term “geometric isomer” refers to E or Zgeometric isomers (e.g., cis or trans) of an alkene double bond. Theterm “positional isomer” refers to structural isomers around a centralring, such as ortho-, meta-, and para-isomers around a benzene ring.

A “tautomer” refers to a molecule wherein a proton shift from one atomof a molecule to another atom of the same molecule is possible. Thecompounds presented herein may, in certain embodiments, exist astautomers. In circumstances where tautomerization is possible, achemical equilibrium of the tautomers will exist. The exact ratio of thetautomers depends on several factors, including physical state,temperature, solvent, and pH. Some examples of tautomeric equilibriuminclude:

“Optional” or “optionally” means that a subsequently described event orcircumstance may or may not occur and that the description includesinstances when the event or circumstance occurs and instances in whichit does not.

“Optionally substituted” or “substituted” means that the referencedgroup may be substituted with one or more additional group(s)individually and independently selected from alkyl, cycloalkyl, aryl,heteroaryl, heterocycloalkyl, —OH, alkoxy, aryloxy, alkylthio, arylthio,alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, —CN, alkyne,C₁-C₆alkylalkyne, halo, acyl, acyloxy, —CO₂H, —CO₂-alkyl, nitro,haloalkyl, fluoroalkyl, and amino, including mono- and di-substitutedamino groups (e.g. —NH₂, —NHR, —N(R)₂), and the protected derivativesthereof. By way of example, an optional substituents may be L^(s)R^(s),wherein each L^(s) is independently selected from a bond, —O—, —C(═O)—,—S—, —S(═O)—, —S(═O)₂—, —NH—, —NHC(O)—, —C(O)NH—, S(═O)₂NH—, —NHS(═O)₂,—OC(O)NH—, —NHC(O)O—, —(C₁-C₆alkyl)-, or —(C₂-C₆alkenyl)-; and eachR^(s) is independently selected from among H, (C₁-C₆alkyl),(C₃-C₈cycloalkyl), aryl, heteroaryl, heterocycloalkyl, andC₁-C₆heteroalkyl. The protecting groups that may form the protectivederivatives of the above substituents are found in sources such asGreene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., JohnWiley & Sons, New York, N.Y., 1999, and Kocienski, Protective Groups,Thieme Verlag, New York, N.Y., 1994, which are incorporated herein byreference for such disclosure.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts. A pharmaceutically acceptable salt of any one of the compoundsdescribed herein is intended to encompass any and all pharmaceuticallysuitable salt forms. Preferred pharmaceutically acceptable salts of thecompounds described herein are pharmaceutically acceptable acid additionsalts and pharmaceutically acceptable base addition salts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid,phosphorous acid, and the like. Also included are salts that are formedwith organic acids such as aliphatic mono- and dicarboxylic acids,phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioicacids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. andinclude, for example, acetic acid, trifluoroacetic acid, propionic acid,glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid,succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid,cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid, and the like. Exemplary saltsthus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites,nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates,metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates,trifluoroacetates, propionates, caprylates, isobutyrates, oxalates,malonates, succinate suberates, sebacates, fumarates, maleates,mandelates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates,phenylacetates, citrates, lactates, malates, tartrates,methanesulfonates, and the like. Also contemplated are salts of aminoacids, such as arginates, gluconates, and galacturonates (see, forexample, Berge S. M. et al., “Pharmaceutical Salts,” Journal ofPharmaceutical Science, 66:1-19 (1997), which is hereby incorporated byreference in its entirety). Acid addition salts of basic compounds maybe prepared by contacting the free base forms with a sufficient amountof the desired acid to produce the salt according to known methods andtechniques.

“Pharmaceutically acceptable base addition salt” refers to those saltsthat retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Pharmaceutically acceptable base addition salts may beformed with metals or amines, such as alkali and alkaline earth metalsor organic amines. Salts derived from inorganic bases include, but arenot limited to, sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Salts derived from organic bases include, but are not limited to, saltsof primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines and basic ionexchange resins, for example, isopropylamine, trimethylamine,diethylamine, triethylamine, tripropylamine, ethanolamine,diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline,betaine, ethylenediamine, ethylenedianiline, N-methylglucamine,glucosamine, methylglucamine, theobromine, purines, piperazine,piperidine, N-ethylpiperidine, polyamine resins and the like. See Bergeet al., supra.

“Pharmaceutically acceptable counterion” refers to an ion thataccompanies an ionic species in order to maintain electric neutralitythat is not biologically or otherwise undesirable.

As used herein, “treatment” or “treating,” or “palliating” or“ameliorating” are used interchangeably herein. These terms refers to anapproach for obtaining beneficial or desired results including but notlimited to therapeutic benefit and/or a prophylactic benefit. By“therapeutic benefit” is meant eradication or amelioration of theunderlying disorder being treated. Also, a therapeutic benefit isachieved with the eradication or amelioration of one or more of thephysiological symptoms associated with the underlying disorder such thatan improvement is observed in the patient, notwithstanding that thepatient may still be afflicted with the underlying disorder. Forprophylactic benefit, the compositions may be administered to a patientat risk of developing a particular disease, or to a patient reportingone or more of the physiological symptoms of a disease, even though adiagnosis of this disease may not have been made.

“Prodrug” is meant to indicate a compound that may be converted underphysiological conditions or by solvolysis to a biologically activecompound described herein. Thus, the term “prodrug” refers to aprecursor of a biologically active compound that is pharmaceuticallyacceptable. A prodrug may be inactive when administered to a subject,but is converted in vivo to an active compound, for example, byhydrolysis. The prodrug compound often offers advantages of solubility,tissue compatibility or delayed release in a mammalian organism (see,e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier,Amsterdam).

A discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugsas Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14, and inBioreversible Carriers in Drug Design, ed. Edward B. Roche, AmericanPharmaceutical Association and Pergamon Press, 1987, both of which areincorporated in full by reference herein.

The term “prodrug” is also meant to include any covalently bondedcarriers, which release the active compound in vivo when such prodrug isadministered to a mammalian subject. Prodrugs of an active compound, asdescribed herein, may be prepared by modifying functional groups presentin the active compound in such a way that the modifications are cleaved,either in routine manipulation or in vivo, to the parent activecompound. Prodrugs include compounds wherein a hydroxy, amino ormercapto group is bonded to any group that, when the prodrug of theactive compound is administered to a mammalian subject, cleaves to forma free hydroxy, free amino or free mercapto group, respectively.Examples of prodrugs include, but are not limited to, acetate, formateand benzoate derivatives of alcohol or amine functional groups in theactive compounds and the like.

Compounds

The compounds, and compositions comprising these compounds, describedherein are useful for preventing, treating, and/or protecting againstsensory hair cell death.

In one embodiment is a compound of Formula (I):

wherein:R₁ is C₆-C₁₀aryl or C₃-C₉heteroaryl, wherein C₆-C₁₀aryl andC₃-C₉heteroaryl are optionally substituted with one or more R₄;R₂ is H, C₁-C₄alkyl, or C₂-C₄alkenyl;R₃ is C₂-C₆alkyl, C₂-C₆alkenyl, C₁-C₄haloalkyl, optionally substitutedC₃-C₆cycloalkyl, optionally substituted C₂-C₇heterocycloalkyl,optionally substituted C₆-C₁₀aryl, —OR₆, —NR₅R₆, —C(O)R₇, —CO₂R₆,—C(O)NR₅R₆, —N(R₅)C(O)R₇, —N(R₅)CO₂R₇, —NHS(O)₂R₇, —S(O)₂NR₅R₆,

orR₂ and R₃ together form an optionally substituted C₂-C₇heterocycloalkylring;each R₄ is independently selected from F, Cl, Br, I, —CN, —NO₂, —CF₃,—OR₉, —OCF₃, —NR₈R₉, —C(O)R₁₀, —CO₂R₉, —C(O)NR₈R₉, —N(R₈)C(O)R₁₀,—N(R₈)CO₂R₁₀, —NHS(O)₂R₁₀, —S(O)₂NR₈R₉, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₇heterocycloalkyl, C₆-C₁₀aryl, andC₃-C₉heteroaryl;R₅ is H, or C₁-C₆alkyl;R₆ is H, C₁-C₆alkyl, optionally substituted C₃-C₆cycloalkyl, optionallysubstituted C₂-C₇heterocycloalkyl, optionally substituted C₆-C₁₀aryl,optionally substituted C₃-C₉heteroaryl, optionally substitutedC₁-C₆alkylC₆-C₁₀aryl, or optionally substitutedC₁-C₆alkylC₃-C₉heteroaryl;R₇ is C₁-C₆alkyl, optionally substituted C₃-C₆cycloalkyl, optionallysubstituted C₂-C₇heterocycloalkyl, optionally substituted C₆-C₁₀aryl,C₃-C₉heteroaryl, optionally substituted C₁-C₆alkylC₆-C₁₀aryl, oroptionally substituted C₁-C₆alkylC₃-C₉heteroaryl;R₈ is H, or C₁-C₆alkyl;R₉ is H, C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, C₆-C₁₀aryl,C₃-C₉heteroaryl, C₁-C₆alkylC₆-C₁₀aryl, or C₁-C₆alkylC₃-C₉heteroaryl;R₁₀ is C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, C₆-C₁₀aryl,C₃-C₉heteroaryl, C₁-C₆alkylC₆-C₁₀aryl, or C₁-C₆alkylC₃-C₉heteroaryl;R₁₁ is H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, C₆-C₁₀aryl, C₃-C₉heteroaryl,C₁-C₆alkylC₃-C₆cycloalkyl, C₁-C₆alkylC₆-C₁₀aryl, orC₁-C₆alkylC₃-C₉heteroaryl;R₁₂ is H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, C₆-C₁₀aryl, C₃-C₉heteroaryl,C₁-C₆alkylC₃-C₆cycloalkyl, C₁-C₆alkylC₆-C₁₀aryl, orC₁-C₆alkylC₃-C₉heteroaryl;or R₁₁ and R₁₂ together with the nitrogen to which they are attachedform an optionally substituted C₂-C₇heterocycloalkyl ring;R₁₃, R₁₄, R₁₅, and R₁₆ are each independently H, or C₁-C₄alkyl;n is an integer selected from 0-4;p is an integer selected from 0-3; andq is an integer selected from 0-3;or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate or hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof.

In another embodiment is a compound of Formula (I) having the structureof Formula (Ia):

In a further embodiment is a compound of Formula (Ia) wherein R₁ isC₆-C₁₀aryl. In a further embodiment is a compound of Formula (Ia)wherein R₁ is phenyl. In a further embodiment is a compound of Formula(Ia) wherein R₁ is phenyl substituted with one or more R₄, and R₄ isindependently selected from F, Cl, Br, I, —CN, —NO₂, —CF₃, —OR₉, —OCF₃,—NR₈R₉, —C(O)R₁₀, —CO₂R₉, C₁-C₆alkyl, and C₁-C₆haloalkyl. In yet afurther embodiment is a compound of Formula (Ia) wherein R₁ is phenylsubstituted with one or more R₄, and R₄ is independently selected fromF, Cl, Br, I, —CN, —CF₃, —OR₉, —OCF₃, —C(O)R₁₀, —CO₂R₉, and C₁-C₆alkyl.In another embodiment is a compound of Formula (Ia) wherein R₁ is4-fluorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 4-bromophenyl,4-iodophenyl, 3-cyanophenyl, 4-trifluoromethylphenyl,4-trifluoromethoxyphenyl, 4-phenoxyphenyl, or 4-benzoylphenyl.

In another embodiment is a compound of Formula (I) or Formula (Ia)wherein R₁₁ and R₁₂ are each H. In another embodiment is a compound ofFormula (I) or Formula (Ia) wherein R₂ is H. In another embodiment is acompound of Formula (I) or Formula (Ia) wherein R₂ is methyl. In anotherembodiment is a compound of Formula (I) or Formula (Ia) wherein R₃ isC₂-C₄alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, —OR₆, —CO₂R₆,—C(O)NR₅R₆, —N(H)C(O)R₇, —N(H)CO₂R₇,

In a further embodiment is a compound of Formula (I) or Formula (Ia)wherein R₆ is H, C₁-C₆alkyl, or C₁-C₆alkylC₆-C₁₀aryl, and R₇ isC₁-C₆alkyl, C₆-C₁₀aryl, C₁-C₆alkylC₆-C₁₀aryl, orC₁-C₆alkylC₃-C₉heteroaryl.

In another embodiment is a compound of Formula (I) or Formula (Ia)wherein R₂ and R₃ together form an optionally substitutedC₂-C₇heterocycloalkyl ring. In a further embodiment is a compound ofFormula (I) or Formula (Ia) wherein R₂ and R₃ together form anoptionally substituted oxetane, pyrrolidine, piperidine, ortetrahydropyran ring.

In another embodiment is a compound of Formula (II):

wherein:X⁻ is a pharmaceutically acceptable counterion;R₁ is C₆-C₁₀aryl or C₃-C₉heteroaryl, wherein C₆-C₁₀aryl andC₃-C₉heteroaryl are optionally substituted with one or more R₄;R₂ is C₁-C₆alkyl, C₁-C₆alkyl-OR₅, or C₁-C₆alkylC₃-C₆cycloalkyl;R₃ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkyl-OR₅, optionally substitutedC₁-C₆alkylC₃-C₆cycloalkyl, optionally substituted C₂-C₇heterocycloalkyl,C₁-C₆alkyl-CO₂R₆, C₁-C₆alkyl-C(O)NR₅R₆, CO₂R₆,

orR₂ and R₃ together with the nitrogen to which they are attached form anoptionally substituted C₂-C₇heterocycloalkyl ring;each R₄ is independently selected from F, Cl, Br, I, —CN, —NO₂, —CF₃,—OR₉, —OCF₃, —NR₈R₉, —C(O)R₁₀, —CO₂R₉, —C(O)NR₈R₉, —N(R₈)C(O)R₁₀,—N(R₈)CO₂R₁₀, —NHS(O)₂R₁₀, —S(O)₂NR₈R₉, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₇heterocycloalkyl, C₆-C₁₀aryl, andC₃-C₉heteroaryl;each R₅ is independently H, or C₁-C₆alkyl;R₆ is H, or C₁-C₆alkyl;R₈ is H, or C₁-C₆alkyl;R₉ is H, C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, C₆-C₁₀aryl,C₃-C₉heteroaryl, C₁-C₆alkylC₆-C₁₀aryl, or C₁-C₆alkylC₃-C₉heteroaryl;R₁₀ is C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, C₆-C₁₀aryl,C₃-C₉heteroaryl, C₁-C₆alkylC₆-C₁₀aryl, or C₁-C₆alkylC₃-C₉heteroaryl;R₁₁ is H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, C₆-C₁₀aryl, C₃-C₉heteroaryl,C₁-C₆alkylC₃-C₆cycloalkyl, C₁-C₆alkylC₆-C₁₀aryl, orC₁-C₆alkylC₃-C₉heteroaryl;R₁₂ is H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, C₆-C₁₀aryl, C₃-C₉heteroaryl,C₁-C₆alkylC₃-C₆cycloalkyl, C₁-C₆alkylC₆-C₁₀aryl, orC₁-C₆alkylC₃-C₉heteroaryl;or R₁₁ and R₁₂ together with the nitrogen to which they are attachedform an optionally substituted C₂-C₇heterocycloalkyl ring;R₁₃, R₁₄, R₁₅, and R₁₆ are each independently H, or C₁-C₄alkyl;p is an integer selected from 0-3; andq is an integer selected from 0-3;or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate or hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof.

In another embodiment is a compound of Formula (II) having the structureof Formula (IIa):

In a further embodiment is a compound of Formula (IIa) wherein R₁ isC₆-C₁₀aryl. In a further embodiment is a compound of Formula (IIa)wherein R₁ is phenyl. In a further embodiment is a compound of Formula(IIa) wherein R₁ is phenyl substituted with one or more R₄, and R₄ isindependently selected from F, Cl, Br, I, —CN, —NO₂, —CF₃, —OR₉, —OCF₃,—NR₈R₉, —C(O)R₁₀, —CO₂R₉, C₁-C₆alkyl, and C₁-C₆haloalkyl. In yet afurther embodiment is a compound of Formula (IIa) wherein R₁ is phenylsubstituted with one or more R₄, and R₄ is independently selected fromF, Cl, Br, I, —CN, —CF₃, —OR₉, —OCF₃, —C(O)R₁₀, —CO₂R₉, and C₁-C₆alkyl.In another embodiment is a compound of Formula (IIa) wherein R₁ is4-chlorophenyl.

In another embodiment is a compound of Formula (II) or Formula (IIa)wherein R₁₁ and R₁₂ are each H. In another embodiment is a compound ofFormula (II) or Formula (IIa) wherein R₃ is C₁-C₆alkyl-CO₂R₆, and R₆ isC₁-C₆alkyl. In another embodiment is a compound of Formula (II) orFormula (IIa) wherein R₃ is C₁-C₆alkylC₃-C₆cycloalkyl. In anotherembodiment is a compound of Formula (II) or Formula (IIa) wherein R₂ ismethyl or ethyl. In another embodiment is a compound of Formula (II) orFormula (IIa) wherein R₂ and R₃ together form an optionally substitutedC₂-C₇heterocycloalkyl ring.

In another embodiment is a compound of Formula (III):

wherein:X is a single bond, double bond, —CH₂—, or —O—;R₁ is C₆-C₁₀aryl or C₃-C₉heteroaryl, wherein C₆-C₁₀aryl andC₃-C₉heteroaryl are optionally substituted with one or more R₄;R₂ is H, C₁-C₆alkyl, C₁-C₆alkyl-OR₆, C₁-C₆alkylC₃-C₆cycloalkyl,C₁-C₆alkylC₂-C₇heterocycloalkyl, C₁-C₆alkyl-CO₂R₆, optionallysubstituted C₁-C₆alkylC₆-C₁₀aryl, or optionally substitutedC₁-C₆alkylC₃-C₉heteroaryl;R₃ are R₅ are each independently H, or C₁-C₆alkyl; orR₃ and R₅ together form an optionally substituted C₃-C₆cycloalkyl ring,optionally substituted C₂-C₇heterocycloalkyl ring, optionallysubstituted C₆-C₁₀aryl ring, or an optionally substitutedC₃-C₉heteroaryl ring;each R₄ is independently selected from F, Cl, Br, I, —CN, —NO₂, —CF₃,—OR₉, —OCF₃, —NR₈R₉, —C(O)R₁₀, —CO₂R₉, —C(O)NR₈R₉, —N(R₈)C(O)R₁₀,—N(R₈)CO₂R₁₀, —NHS(O)₂R₁₀, —S(O)₂NR₈R₉, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₇heterocycloalkyl, C₆-C₁₀aryl, andC₃-C₉heteroaryl;R₆ is H, or C₁-C₆alkyl;R₈ is H, or C₁-C₆alkyl;R₉ is H, C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, C₆-C₁₀aryl,C₃-C₉heteroaryl, C₁-C₆alkylC₆-C₁₀aryl, or C₁-C₆alkylC₃-C₉heteroaryl;R₁₀ is C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, C₆-C₁₀aryl,C₃-C₉heteroaryl, C₁-C₆alkylC₆-C₁₀aryl, or C₁-C₆alkylC₃-C₉heteroaryl;R₁₁ is H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, C₆-C₁₀aryl, C₃-C₉heteroaryl,C₁-C₆alkylC₃-C₆cycloalkyl, C₁-C₆alkylC₆-C₁₀aryl, orC₁-C₆alkylC₃-C₉heteroaryl;R₁₂ is H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, C₆-C₁₀aryl, C₃-C₉heteroaryl,C₁-C₆alkylC₃-C₆cycloalkyl, C₁-C₆alkylC₆-C₁₀aryl, orC₁-C₆alkylC₃-C₉heteroaryl;or R₁₁ and R₁₂ together with the nitrogen to which they are attachedform an optionally substituted C₂-C₇heterocycloalkyl ring; andR₁₃ are R₁₄ are each independently H, or C₁-C₆alkyl;or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate or hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof.

In another embodiment is a compound of Formula (III) wherein R₁ isC₆-C₁₀aryl. In a further embodiment is a compound of Formula (III)wherein R₁ is phenyl. In a further embodiment is a compound of Formula(III) wherein R₁ is phenyl substituted with one or more R₄, and R₄ isindependently selected from F, Cl, Br, I, —CN, —NO₂, —CF₃, —OR₉, —OCF₃,—NR₈R₉, —C(O)R₁₀, —CO₂R₉, C₁-C₆alkyl, and C₁-C₆haloalkyl. In yet afurther embodiment is a compound of Formula (III) wherein R₁ is phenylsubstituted with one or more R₄, and R₄ is independently selected fromF, Cl, Br, I, —CN, —CF₃, —OR₉, —OCF₃, —C(O)R₁₀, —CO₂R₉, and C₁-C₆alkyl.In another embodiment is a compound of Formula (III) wherein R₁ is4-chlorophenyl.

In another embodiment is a compound of Formula (III) wherein R₁₁ and R₁₂are each H. In another embodiment is a compound of Formula (III) whereinR₂ is H. In another embodiment is a compound of Formula (III) wherein R₂is C₁-C₆alkyl. In another embodiment is a compound of Formula (III)wherein R₁₃ and R₁₄ are each H. In another embodiment is a compound ofFormula (III) wherein R₁₃ and R₁₄ are each CH₃. In another embodiment isa compound of Formula (III) wherein R₃ and R₅ are each H.

In another embodiment is a compound of Formula (IV):

wherein:R₁ is C₆-C₁₀aryl or C₃-C₉heteroaryl, wherein C₆-C₁₀aryl andC₃-C₉heteroaryl are optionally substituted with one or more R₄;R₂ is H, —CH₃, —CH₂CH₃, or —CH(CH₃)₂;each R₄ is independently selected from F, Br, I, —CN, —NO₂, —OR₉, —OCF₃,—NR₈R₉, —C(O)NR₈R₉, —N(R₈)C(O)R₁₀, —N(R₈)CO₂R₁₀, —NHS(O)₂R₁₀,—S(O)₂NR₈R₉, C₂-C₆alkyl, C₃-C₆cycloalkyl, C₁-C₆heteroalkyl,C₂-C₇heterocycloalkyl, C₆-C₁₀aryl, and C₃-C₉heteroaryl;R₈ is H, or C₁-C₆alkyl;R₉ is H, C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, C₆-C₁₀aryl,C₃-C₉heteroaryl, C₁-C₆alkylC₆-C₁₀aryl, or C₁-C₆alkylC₃-C₉heteroaryl;R₁₀ is C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, C₆-C₁₀aryl,C₃-C₉heteroaryl, C₁-C₆alkylC₆-C₁₀aryl, or C₁-C₆alkylC₃-C₉heteroaryl;R₁₁ is H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, C₆-C₁₀aryl, C₃-C₉heteroaryl,C₁-C₆alkylC₃-C₆cycloalkyl, C₁-C₆alkylC₆-C₁₀aryl, orC₁-C₆alkylC₃-C₉heteroaryl;R₁₂ is H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, C₆-C₁₀aryl, C₃-C₉heteroaryl,C₁-C₆alkylC₃-C₆cycloalkyl, C₁-C₆alkylC₆-C₁₀aryl, orC₁-C₆alkylC₃-C₉heteroaryl;or R₁₁ and R₁₂ together with the nitrogen to which they are attachedform an optionally substituted C₂-C₇heterocycloalkyl ring;p is an integer selected from 0-3; andq is an integer selected from 0-3;or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate or hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof.

In another embodiment is a compound of Formula (IV) having the structureof Formula (IVa):

In a further embodiment is a compound of Formula (IVa) wherein R₁ isC₆-C₁₀aryl. In a further embodiment is a compound of Formula (IVa)wherein R₁ is phenyl. In a further embodiment is a compound of Formula(IVa) wherein R₁ is phenyl substituted with one or more R₄, and R₄ isindependently selected from F, Br, I, —CN, —OR₉, —OCF₃, —NR₈R₉,—C(O)R₁₀, —CO₂R₉, and C₂-C₆alkyl. In yet a further embodiment is acompound of Formula (IVa) wherein R₁ is phenyl substituted with one ormore R₄, and R₄ is independently selected from F, Br, I, —CN, —CF₃,—OR₉, —OCF₃, —C(O)R₁₀, —CO₂R₉, and C₂-C₆alkyl.

In another embodiment is a compound of Formula (IV) or Formula (IVa)wherein R₁₁ and R₁₂ are each H. In another embodiment is a compound ofFormula (IV) or Formula (IVa) wherein R₂ is H. In another embodiment isa compound of Formula (IV) or Formula (IVa) wherein R₂ is —CH₃. Inanother embodiment is a compound of Formula (IV) or Formula (IVa)wherein R₂ is —CH₂CH₃. In another embodiment is a compound of Formula(IV) or Formula (IVa) wherein R₂ is —CH(CH₃)₂.

In another embodiment is a compound of Formula (V):

wherein:R₁ is C₆-C₁₀aryl or C₃-C₉heteroaryl, wherein C₆-C₁₀aryl andC₃-C₉heteroaryl are optionally substituted with one or more R₄;each R₂ is independently H, or C₁-C₄alkyl;R₃ is H, C₁-C₆alkyl, C₁-C₆haloalkyl, optionally substitutedC₃-C₆cycloalkyl, optionally substituted C₂-C₇heterocycloalkyl,optionally substituted C₆-C₁₀aryl, optionally substitutedC₃-C₉heteroaryl, —OR₆, —NR₅R₆, —C(O)R₇, —CO₂R₆, —C(O)NR₅R₆,—N(R₅)C(O)R₇, —N(R₅)CO₂R₇, —NHS(O)₂R₇, —S(O)₂NR₅R₆,

orR₂ and R₃ together form an optionally substituted C₂-C₇heterocycloalkylring;each R₄ is independently selected from F, Cl, Br, I, —CN, —NO₂, —CF₃,—OR₉, —OCF₃, —NR₈R₉, —C(O)R₁₀, —CO₂R₉, —C(O)NR₈R₉, —N(R₈)C(O)R₁₀,—N(R₈)CO₂R₁₀, —NHS(O)₂R₁₀, —S(O)₂NR₈R₉, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₇heterocycloalkyl, C₆-C₁₀aryl, andC₃-C₉heteroaryl;R₅ is H, or C₁-C₆alkyl;R₆ is H, C₁-C₆alkyl, optionally substituted C₃-C₆cycloalkyl, optionallysubstituted C₂-C₇heterocycloalkyl, optionally substituted C₆-C₁₀aryl,optionally substituted C₃-C₉heteroaryl, optionally substitutedC₁-C₆alkylC₆-C₁₀aryl, or optionally substitutedC₁-C₆alkylC₃-C₉heteroaryl;R₇ is C₁-C₆alkyl, optionally substituted C₃-C₆cycloalkyl, optionallysubstituted C₂-C₇heterocycloalkyl, optionally substituted C₆-C₁₀aryl,C₃-C₉heteroaryl, optionally substituted C₁-C₆alkylC₆-C₁₀aryl, oroptionally substituted C₁-C₆alkylC₃-C₉heteroaryl;R₈ is H, or C₁-C₆alkyl;R₉ is H, C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, C₆-C₁₀aryl,C₃-C₉heteroaryl, C₁-C₆alkylC₆-C₁₀aryl, or C₁-C₆alkylC₃-C₉heteroaryl;R₁₀ is C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, C₆-C₁₀aryl,C₃-C₉heteroaryl, C₁-C₆alkylC₆-C₁₀aryl, or C₁-C₆alkylC₃-C₉heteroaryl;R₁₁ is H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, C₆-C₁₀aryl, C₃-C₉heteroaryl,C₁-C₆alkylC₃-C₆cycloalkyl, C₁-C₆alkylC₆-C₁₀aryl, orC₁-C₆alkylC₃-C₉heteroaryl;R₁₂ is H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, C₆-C₁₀aryl, C₃-C₉heteroaryl,C₁-C₆alkylC₃-C₆cycloalkyl, C₁-C₆alkylC₆-C₁₀aryl, orC₁-C₆alkylC₃-C₉heteroaryl;or R₁₁ and R₁₂ together with the nitrogen to which they are attachedform an optionally substituted C₂-C₇heterocycloalkyl ring;R₁₃, R₁₄, R₁₅, and R₁₆ are each independently H, or C₁-C₄alkyl, whereinat least one of R₁₃, R₁₄, R₁₅, and R₁₆ is not H; or R₃ and R₁₃ togetherform an optionally substituted C₂-C₇heterocycloalkyl ring; or R₃ and R₁₅together form an optionally substituted C₂-C₇heterocycloalkyl ring; andn is an integer selected from 0-5;p is an integer selected from 0-3; andq is an integer selected from 0-3;or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate or hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof.

In another embodiment is a compound of Formula (V) having the structureof Formula (Va):

In a further embodiment is a compound of Formula (Va) wherein R₁ isC₆-C₁₀aryl. In a further embodiment is a compound of Formula (Va)wherein R₁ is phenyl. In a further embodiment is a compound of Formula(Va) wherein R₁ is phenyl substituted with one or more R₄, and R₄ isindependently selected from F, Cl, Br, I, —CN, —NO₂, —CF₃, —OR₉, —OCF₃,—NR₈R₉, —C(O)R₁₀, —CO₂R₉, C₁-C₆alkyl, and C₁-C₆haloalkyl. In yet afurther embodiment is a compound of Formula (Va) wherein R₁ is phenylsubstituted with one or more R₄, and R₄ is independently selected fromF, Cl, Br, I, —CN, —CF₃, —OR₉, —OCF₃, —C(O)R₁₀, —CO₂R₉, and C₁-C₆alkyl.In another embodiment is a compound of Formula (Va) wherein R₁ is4-fluorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 4-bromophenyl,4-iodophenyl, 3-cyanophenyl, 4-trifluoromethylphenyl,4-trifluoromethoxyphenyl, 4-phenoxyphenyl, or 4-benzoylphenyl.

In another embodiment is a compound of Formula (V) or Formula (Va)wherein R₁₁ and R₁₂ are each H. In another embodiment is a compound ofFormula (V) or Formula (Va) wherein n is 0. In another embodiment is acompound of Formula (V) or Formula (Va) wherein R₃ is H. In anotherembodiment is a compound of Formula (V) or Formula (Va) wherein R₃ ismethyl. In another embodiment is a compound of Formula (V) or Formula(Va) wherein R₃ is C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl,—OR₆, —CO₂R₆, —C(O)NR₅R₆, —N(H)C(O)R₇, —N(H)CO₂R₇,

In another embodiment is a compound of Formula (V) or Formula (Va)wherein R₆ is H, C₁-C₆alkyl, or C₁-C₆alkylC₆-C₁₀aryl, and R₇ isC₁-C₆alkyl, C₆-C₁₀aryl, C₁-C₆alkylC₆-C₁₀aryl, orC₁-C₆alkylC₃-C₉heteroaryl.

In another embodiment is a compound of Formula (VI):

wherein:X is a single bond, double bond, —CH₂—, or —O—;R₁ is C₆-C₁₀aryl or C₃-C₉heteroaryl, wherein C₆-C₁₀aryl andC₃-C₉heteroaryl are optionally substituted with one or more R₄;R_(2a) is C₁-C₆alkyl, C₁-C₆alkyl-OR₅, or C₁-C₆alkylC₃-C₆cycloalkyl;R₂ is C₁-C₆alkyl, C₁-C₆alkyl-OR₆, C₁-C₆alkylC₃-C₆cycloalkyl, orC₁-C₆alkyl-CO₂R₆;R₃ are R₅ are each independently H, or C₁-C₆alkyl; orR₃ and R₅ together form an optionally substituted C₃-C₆cycloalkyl ring,optionally substituted C₂-C₇heterocycloalkyl ring, optionallysubstituted C₆-C₁₀aryl ring, or an optionally substitutedC₃-C₉heteroaryl ring;each R₄ is independently selected from F, Cl, Br, I, —CN, —NO₂, —CF₃,—OR₉, —OCF₃, —NR₈R₉, —C(O)R₁₀, —CO₂R₉, —C(O)NR₈R₉, —N(R₈)C(O)R₁₀,—N(R₈)CO₂R₁₀, —NHS(O)₂R₁₀, —S(O)₂NR₈R₉, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₇heterocycloalkyl, C₆-C₁₀aryl, andC₃-C₉heteroaryl;R₆ is H, or C₁-C₆alkyl;R₈ is H, or C₁-C₆alkyl;R₉ is H, C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, C₆-C₁₀aryl,C₃-C₉heteroaryl, C₁-C₆alkylC₆-C₁₀aryl, or C₁-C₆alkylC₃-C₉heteroaryl;R₁₀ is C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, C₆-C₁₀aryl,C₃-C₉heteroaryl, C₁-C₆alkylC₆-C₁₀aryl, or C₁-C₆alkylC₃-C₉heteroaryl;R₁₁ is H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, C₆-C₁₀aryl, C₃-C₉heteroaryl,C₁-C₆alkylC₃-C₆cycloalkyl, C₁-C₆alkylC₆-C₁₀aryl, orC₁-C₆alkylC₃-C₉heteroaryl;R₁₂ is H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, C₆-C₁₀aryl, C₃-C₉heteroaryl,C₁-C₆alkylC₃-C₆cycloalkyl, C₁-C₆alkylC₆-C₁₀aryl, orC₁-C₆alkylC₃-C₉heteroaryl;or R₁₁ and R₁₂ together with the nitrogen to which they are attachedform an optionally substituted C₂-C₇heterocycloalkyl ring; andR₁₃ are R₁₄ are each independently H, or C₁-C₆alkyl;or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate or hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof.

In another embodiment is a compound of Formula (VI) wherein R₁ isC₆-C₁₀aryl. In a further embodiment is a compound of Formula (VI)wherein R₁ is phenyl. In a further embodiment is a compound of Formula(VI) wherein R₁ is phenyl substituted with one or more R₄, and R₄ isindependently selected from F, Cl, Br, I, —CN, —NO₂, —CF₃, —OR₉, —OCF₃,—NR₈R₉, —C(O)R₁₀, —CO₂R₉, C₁-C₆alkyl, and C₁-C₆haloalkyl. In yet afurther embodiment is a compound of Formula (VI) wherein R₁ is phenylsubstituted with one or more R₄, and R₄ is independently selected fromF, Cl, Br, I, —CN, —CF₃, —OR₉, —OCF₃, —C(O)R₁₀, —CO₂R₉, and C₁-C₆alkyl.In another embodiment is a compound of Formula (VI) wherein R₁ is4-chlorophenyl.

In another embodiment is a compound of Formula (VI) wherein R₁₁ and R₁₂are each H. In another embodiment is a compound of Formula (VI) whereinR₂ is C₁-C₆alkyl-CO₂R₆. In another embodiment is a compound of Formula(VI) wherein R_(2a) is C₁-C₆alkyl. In another embodiment is a compoundof Formula (VI) wherein R₁₃ and R₁₄ are each H. In another embodiment isa compound of Formula (VI) wherein R₁₃ and R₁₄ are each CH₃. In anotherembodiment is a compound of Formula (VI) wherein R₃ and R₅ are each H.

In another embodiment is a compound of Formula (VII):

wherein:R₁ is C₆-C₁₀aryl or C₃-C₉heteroaryl, wherein C₆-C₁₀aryl andC₃-C₉heteroaryl are optionally substituted with one or more R₄;R₂ is H, C₁-C₆alkyl, C₁-C₆alkyl-NR₅R₆, C₁-C₆alkyl-OR₅, orC₁-C₆alkylC₃-C₆cycloalkyl;R₃ is —NR₅R₆, C₁-C₆alkyl-NR₅R₆, C₁-C₆haloalkyl, C₁-C₆alkyl-OR₅,optionally substituted C₁-C₆alkylC₃-C₆cycloalkyl, optionally substitutedC₂-C₇heterocycloalkyl, C₁-C₆alkyl-CO₂R₆, C₁-C₆alkyl-C(O)NR₅R₆,

R₂ and R₃ together with the carbon atom to which they are attached forman optionally substituted C₂-C₇heterocycloalkyl ring;each R₄ is independently selected from F, Cl, Br, I, —CN, —NO₂, —CF₃,—OR₉, —OCF₃, —NR₈R₉, —C(O)R₁₀, —CO₂R₉, —C(O)NR₈R₉, —N(R₈)C(O)R₁₀,—N(R₈)CO₂R₁₀, —NHS(O)₂R₁₀, —S(O)₂NR₈R₉, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₇heterocycloalkyl, C₆-C₁₀aryl, andC₃-C₉heteroaryl;each R₅ is independently H, or C₁-C₆alkyl;R₆ is H, or C₁-C₆alkyl;R₈ is H, or C₁-C₆alkyl;R₉ is H, C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, C₆-C₁₀aryl,C₃-C₉heteroaryl, C₁-C₆alkylC₆-C₁₀aryl, or C₁-C₆alkylC₃-C₉heteroaryl;R₁₀ is C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, C₆-C₁₀aryl,C₃-C₉heteroaryl, C₁-C₆alkylC₆-C₁₀aryl, or C₁-C₆alkylC₃-C₉heteroaryl;R₁₁ is H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, C₆-C₁₀aryl, C₃-C₉heteroaryl,C₁-C₆alkylC₃-C₆cycloalkyl, C₁-C₆alkylC₆-C₁₀aryl, orC₁-C₆alkylC₃-C₉heteroaryl;R₁₂ is H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, C₆-C₁₀aryl, C₃-C₉heteroaryl,C₁-C₆alkylC₃-C₆cycloalkyl, C₁-C₆alkylC₆-C₁₀aryl, orC₁-C₆alkylC₃-C₉heteroaryl;or R₁₁ and R₁₂ together with the nitrogen to which they are attachedform an optionally substituted C₂-C₇heterocycloalkyl ring;R₁₃, R₁₄, R₁₅, and R₁₆ are each independently H, or C₁-C₄alkyl;p is an integer selected from 0-3; andq is an integer selected from 0-3;or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate or hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof.

In another embodiment is a compound of Formula (VII) having thestructure of Formula (VIIa):

In a further embodiment is a compound of Formula (VIIa) wherein R₁ isC₆-C₁₀aryl. In a further embodiment is a compound of Formula (VIIa)wherein R₁ is phenyl. In a further embodiment is a compound of Formula(VIIa) wherein R₁ is phenyl substituted with one or more R₄, and R₄ isindependently selected from F, Cl, Br, I, —CN, —NO₂, —CF₃, —OR₉, —OCF₃,—NR₈R₉, —C(O)R₁₀, —CO₂R₉, C₁-C₆alkyl, and C₁-C₆haloalkyl. In yet afurther embodiment is a compound of Formula (VIIa) wherein R₁ is phenylsubstituted with one or more R₄, and R₄ is independently selected fromF, Cl, Br, I, —CN, —CF₃, —OR₉, —OCF₃, —C(O)R₁₀, —CO₂R₉, and C₁-C₆alkyl.In another embodiment is a compound of Formula (VIIa) wherein R₁ is4-chlorophenyl.

In another embodiment is a compound of Formula (VII) or Formula (VIIa)wherein R₁₁ and R₁₂ are each H. In another embodiment is a compound ofFormula (VII) or Formula (VIIa) wherein R₂ and R₃ together with thecarbon atom to which they are attached form an optionally substitutedC₂-C₇heterocycloalkyl ring. In another embodiment is a compound ofFormula (VII) or Formula (VIIa) wherein R₂ is H, and R₃ is —NR₅R₆. Inanother embodiment is a compound of Formula (VII) or Formula (VIIa)wherein R₂ is H, and R₃ is optionally substituted C₂-C₇heterocycloalkyl.

In some embodiments is a compound of Formula (I)-(VII) having thestructure:

or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate or hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof.Synthesis of Compounds

In some embodiments, the synthesis of compounds described herein areaccomplished using means described in the chemical literature, using themethods described herein, or by a combination thereof. In addition,solvents, temperatures and other reaction conditions presented hereinmay vary.

In other embodiments, the starting materials and reagents used for thesynthesis of the compounds described herein are synthesized or areobtained from commercial sources, such as, but not limited to,Sigma-Aldrich, FischerScientific (Fischer Chemicals), and AcrosOrganics.

In further embodiments, the compounds described herein, and otherrelated compounds having different substituents are synthesized usingtechniques and materials described herein as well as those that arerecognized in the field, such as described, for example, in Fieser andFieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley andSons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplementals (Elsevier Science Publishers, 1989); Organic Reactions,Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive OrganicTransformations (VCH Publishers Inc., 1989), March, Advanced OrganicChemistry 4^(th) Ed., (Wiley 1992); Carey and Sundberg, Advanced OrganicChemistry 4^(th) Ed., Vols. A and B (Plenum 2000, 2001), and Green andWuts, Protective Groups in Organic Synthesis 3^(rd) Ed., (Wiley 1999)(all of which are incorporated by reference for such disclosure).General methods for the preparation of compound as disclosed herein maybe derived from reactions and the reactions may be modified by the useof appropriate reagents and conditions, for the introduction of thevarious moieties found in the formulae as provided herein.

Use of Protecting Groups

In the reactions described, it may be necessary to protect reactivefunctional groups, for example hydroxy, amino, imino, thio or carboxygroups, where these are desired in the final product, in order to avoidtheir unwanted participation in reactions. Protecting groups are used toblock some or all of the reactive moieties and prevent such groups fromparticipating in chemical reactions until the protective group isremoved. It is preferred that each protective group be removable by adifferent means. Protective groups that are cleaved under totallydisparate reaction conditions fulfill the requirement of differentialremoval.

Protective groups are optionally removed by acid, base, reducingconditions (such as, for example, hydrogenolysis), and/or oxidativeconditions. Groups such as trityl, dimethoxytrityl, acetal andt-butyldimethylsilyl are acid labile and may be used to protect carboxyand hydroxy reactive moieties in the presence of amino groups protectedwith Cbz groups, which are removable by hydrogenolysis, and Fmoc groups,which are base labile. Carboxylic acid and hydroxy reactive moieties maybe blocked with base labile groups such as, but not limited to, methyl,ethyl, and acetyl in the presence of amines blocked with acid labilegroups such as t-butyl carbamate or with carbamates that are both acidand base stable but hydrolytically removable.

Carboxylic acid and hydroxy reactive moieties may also be blocked withhydrolytically removable protective groups such as the benzyl group,while amine groups capable of hydrogen bonding with acids may be blockedwith base labile groups such as Fmoc. Carboxylic acid reactive moietiesmay be protected by conversion to simple ester compounds as exemplifiedherein, which include conversion to alkyl esters, or they may be blockedwith oxidatively-removable protective groups such as2,4-dimethoxybenzyl, while co-existing amino groups may be blocked withfluoride labile silyl carbamates.

Allyl blocking groups are useful in then presence of acid- andbase-protecting groups since the former are stable and are optionallysubsequently removed by metal or pi-acid catalysts. For example, anallyl-blocked carboxylic acid are optionally deprotected with aPd⁰-catalyzed reaction in the presence of acid labile t-butyl carbamateor base-labile acetate amine protecting groups. Yet another form ofprotecting group is a resin to which a compound or intermediate may beattached. As long as the residue is attached to the resin, thatfunctional group is blocked and cannot react. Once released from theresin, the functional group is available to react.

Typically blocking/protecting groups may be selected from:

Other protecting groups, plus a detailed description of techniquesapplicable to the creation of protecting groups and their removal aredescribed in Greene and Wuts, Protective Groups in Organic Synthesis,3rd Ed., John Wiley & Sons, New York, N.Y., 1999, and Kocienski,Protective Groups, Thieme Verlag, New York, N.Y., 1994, which areincorporated herein by reference for such disclosure).

Pharmaceutical Compositions and Methods of Administration

Pharmaceutical compositions may be formulated in a conventional mannerusing one or more physiologically acceptable carriers includingexcipients and auxiliaries which facilitate processing of the activecompounds into preparations which are optionally used pharmaceutically.Proper formulation is dependent upon the route of administration chosen.Additional details about suitable excipients for pharmaceuticalcompositions described herein may be found, for example, in Remington:The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: MackPublishing Company, 1995); Hoover, John E., Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. andLachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York,N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems,Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated byreference for such disclosure.

A pharmaceutical composition, as used herein, refers to a mixture of acompound of Formula (I)-(VII) described herein, with other chemicalcomponents, such as carriers, stabilizers, diluents, dispersing agents,suspending agents, thickening agents, and/or excipients. Thepharmaceutical composition facilitates administration of the compound toan organism. In practicing the methods of treatment or use providedherein, therapeutically effective amounts of compounds described hereinare administered in a pharmaceutical composition to a mammal having adisease, disorder, or condition to be treated. In some embodiments, themammal is a human. A therapeutically effective amount depends on theseverity of the disease, the age and relative health of the subject, thepotency of the compound used and other factors. The compounds of Formula(I)-(VII) are optionally used singly or in combination with one or moretherapeutic agents as components of mixtures (as in combinationtherapy).

The pharmaceutical formulations described herein are optionallyadministered to a subject by multiple administration routes, includingbut not limited to, oral, parenteral (e.g., intravenous, subcutaneous,intramuscular), intranasal, buccal, topical, rectal, or transdermaladministration routes. Moreover, the pharmaceutical compositionsdescribed herein, which include a compound of Formula (I)-(VII)described herein, are optionally formulated into any suitable dosageform, including but not limited to, aqueous oral dispersions, liquids,gels, syrups, elixirs, slurries, suspensions, aerosols, controlledrelease formulations, fast melt formulations, effervescent formulations,lyophilized formulations, tablets, powders, pills, dragees, capsules,delayed release formulations, extended release formulations, pulsatilerelease formulations, multiparticulate formulations, and mixed immediaterelease and controlled release formulations.

One may administer the compounds and/or compositions in a local ratherthan systemic manner, for example, via injection of the compounddirectly into an organ or tissue, often in a depot preparation orsustained release formulation. Such long acting formulations may beadministered by implantation (for example subcutaneously orintramuscularly) or by intramuscular injection. Furthermore, one mayadminister the drug in a targeted drug delivery system, for example, ina liposome coated with organ-specific antibody. The liposomes will betargeted to and taken up selectively by the organ. In addition, the drugmay be provided in the form of a rapid release formulation, in the formof an extended release formulation, or in the form of an intermediaterelease formulation.

Pharmaceutical compositions including a compound described herein may bemanufactured in a conventional manner, such as, by way of example only,by means of conventional mixing, dissolving, granulating, dragee-making,levigating, emulsifying, encapsulating, entrapping or compressionprocesses.

The pharmaceutical compositions will include at least one compound ofFormula (I)-(VII) described herein, as an active ingredient in free-acidor free-base form, or in a pharmaceutically acceptable salt form. Inaddition, the methods and pharmaceutical compositions described hereininclude the use of crystalline forms (also known as polymorphs), as wellas active metabolites of these compounds having the same type ofactivity. In some situations, compounds may exist as tautomers. Alltautomers are included within the scope of the compounds presentedherein. Additionally, many of the compounds described herein exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. The solvated forms of thecompounds presented herein are also considered to be disclosed herein.

In certain embodiments, compositions provided herein may also includeone or more preservatives to inhibit microbial activity. Suitablepreservatives include quaternary ammonium compounds such as benzalkoniumchloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.

Pharmaceutical preparations for oral use are optionally obtained bymixing one or more solid excipient with one or more of the compounds ofFormula (I)-(VII) described herein, optionally grinding the resultingmixture, and processing the mixture of granules, after adding suitableauxiliaries, if desired, to obtain tablets, pills, or capsules. Suitableexcipients include, for example, fillers such as sugars, includinglactose, sucrose, mannitol, or sorbitol; cellulose preparations such as,for example, maize starch, wheat starch, rice starch, potato starch,gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or otherssuch as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. Ifdesired, disintegrating agents may be added, such as the cross-linkedcroscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or asalt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical preparations that are used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules optionally contain the active ingredients in admixture withfiller such as lactose, binders such as starches, and/or lubricants suchas talc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added.

In some embodiments, the solid dosage forms disclosed herein may be inthe form of a tablet, (including a suspension tablet, a fast-melttablet, a bite-disintegration tablet, a rapid-disintegration tablet, aneffervescent tablet, or a caplet), a pill, a powder (including a sterilepackaged powder, a dispensable powder, or an effervescent powder), acapsule (including both soft or hard capsules, e.g., capsules made fromanimal-derived gelatin or plant-derived HPMC, or “sprinkle capsules”),solid dispersion, solid solution, bioerodible dosage form, controlledrelease formulations, pulsatile release dosage forms, multiparticulatedosage forms, pellets, granules, or an aerosol. In other embodiments,the pharmaceutical formulation is in the form of a powder. In stillother embodiments, the pharmaceutical formulation is in the form of atablet, including but not limited to, a fast-melt tablet. Additionally,pharmaceutical formulations of the compounds described herein may beadministered as a single capsule or in multiple capsule dosage form. Insome embodiments, the pharmaceutical formulation is administered in two,or three, or four, capsules or tablets.

In some embodiments, solid dosage forms, e.g., tablets, effervescenttablets, and capsules, are prepared by mixing particles of a compound ofFormula (I)-(VII) described herein, with one or more pharmaceuticalexcipients to form a bulk blend composition. When referring to thesebulk blend compositions as homogeneous, it is meant that the particlesof the compound of Formula (I)-(VII) described herein, are dispersedevenly throughout the composition so that the composition may besubdivided into equally effective unit dosage forms, such as tablets,pills, and capsules. The individual unit dosages may also include filmcoatings, which disintegrate upon oral ingestion or upon contact withdiluent. These formulations are optionally manufactured by conventionalpharmacological techniques.

The pharmaceutical solid dosage forms described herein include acompound of Formula (I)-(VII) described herein, and optionally one ormore pharmaceutically acceptable additives such as a compatible carrier,binder, filling agent, suspending agent, flavoring agent, sweeteningagent, disintegrating agent, dispersing agent, surfactant, lubricant,colorant, diluent, solubilizer, moistening agent, plasticizer,stabilizer, penetration enhancer, wetting agent, anti-foaming agent,antioxidant, preservative, or one or more combination thereof. In stillother aspects, using standard coating procedures, such as thosedescribed in Remington's Pharmaceutical Sciences, 20th Edition (2000), afilm coating is provided around the formulation of the compounddescribed herein. In one embodiment, some or all of the particles of thecompound described herein are coated. In another embodiment, some or allof the particles of the compound described herein are microencapsulated.In still another embodiment, the particles of the compound describedherein are not microencapsulated and are uncoated.

Suitable carriers for use in the solid dosage forms described hereininclude, but are not limited to, acacia, gelatin, colloidal silicondioxide, calcium glycerophosphate, calcium lactate, maltodextrin,glycerine, magnesium silicate, sodium caseinate, soy lecithin, sodiumchloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyllactylate, carrageenan, monoglyceride, diglyceride, pregelatinizedstarch, hydroxypropylmethylcellulose, hydroxypropylmethylcelluloseacetate stearate, sucrose, microcrystalline cellulose, lactose, mannitoland the like.

Suitable filling agents for use in the solid dosage forms describedherein include, but are not limited to, lactose, calcium carbonate,calcium phosphate, dibasic calcium phosphate, calcium sulfate,microcrystalline cellulose, cellulose powder, dextrose, dextrates,dextran, starches, pregelatinized starch, hydroxypropylmethycellulose(HPMC), hydroxypropylmethycellulose phthalate,hydroxypropylmethylcellulose acetate stearate (HPMCAS), sucrose,xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethyleneglycol, and the like.

In order to release the compound of Formula (I)-(VII) from a soliddosage form matrix as efficiently as possible, disintegrants are oftenused in the formulation, especially when the dosage forms are compressedwith binder. Disintegrants help rupturing the dosage form matrix byswelling or capillary action when moisture is absorbed into the dosageform. Suitable disintegrants for use in the solid dosage forms describedherein include, but are not limited to, natural starch such as cornstarch or potato starch, a pregelatinized starch such as National 1551or Amijel®, or sodium starch glycolate such as Promogel® or Explotab®, acellulose such as a wood product, methylcrystalline cellulose, e.g.,Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100,Emcocel®, Vivacel®, Ming Tia®, and Solka-Floc®, methylcellulose,croscarmellose, or a cross-linked cellulose, such as cross-linked sodiumcarboxymethylcellulose (Ac-Di-Sol®), cross-linkedcarboxymethylcellulose, or cross-linked croscarmellose, a cross-linkedstarch such as sodium starch glycolate, a cross-linked polymer such ascrospovidone, a cross-linked polyvinylpyrrolidone, alginate such asalginic acid or a salt of alginic acid such as sodium alginate, a claysuch as Veegum® HV (magnesium aluminum silicate), a gum such as agar,guar, locust bean, Karaya, pectin, or tragacanth, sodium starchglycolate, bentonite, a natural sponge, a surfactant, a resin such as acation-exchange resin, citrus pulp, sodium lauryl sulfate, sodium laurylsulfate in combination starch, and the like.

Binders impart cohesiveness to solid oral dosage form formulations: forpowder filled capsule formulation, they aid in plug formation that areoptionally filled into soft or hard shell capsules and for tabletformulation, they ensure the tablet remaining intact after compressionand help assure blend uniformity prior to a compression or fill step.Materials suitable for use as binders in the solid dosage formsdescribed herein include, but are not limited to,carboxymethylcellulose, methylcellulose (e.g., Methocel®),hydroxypropylmethylcellulose (e.g. Hypromellose USP Pharmacoat-603,hydroxypropylmethylcellulose acetate stearate (Aqoate HS-LF and HS),hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®),ethylcellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g.,Avicel®), microcrystalline dextrose, amylose, magnesium aluminumsilicate, polysaccharide acids, bentonites, gelatin,polyvinylpyrrolidone/vinyl acetate copolymer, crospovidone, povidone,starch, pregelatinized starch, tragacanth, dextrin, a sugar, such assucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol,xylitol (e.g., Xylitab®), lactose, a natural or synthetic gum such asacacia, tragacanth, ghatti gum, mucilage of isapol husks, starch,polyvinylpyrrolidone (e.g., Povidone® CL, Kollidon® CL, Polyplasdone®XL-10, and Povidone® K-12), larch arabogalactan, Veegum®, polyethyleneglycol, waxes, sodium alginate, and the like.

In general, binder levels of 20-70% are used in powder-filled gelatincapsule formulations. Binder usage level in tablet formulations varieswhether direct compression, wet granulation, roller compaction, or usageof other excipients such as fillers which itself can act as moderatebinder. In some embodiments, formulators determine the binder level forthe formulations, but binder usage level of up to 70% in tabletformulations is common.

Suitable lubricants or glidants for use in the solid dosage formsdescribed herein include, but are not limited to, stearic acid, calciumhydroxide, talc, corn starch, sodium stearyl fumerate, alkali-metal andalkaline earth metal salts, such as aluminum, calcium, magnesium, zinc,stearic acid, sodium stearates, magnesium stearate, zinc stearate,waxes, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodiumchloride, leucine, a polyethylene glycol or a methoxypolyethylene glycolsuch as Carbowax™, PEG 4000, PEG 5000, PEG 6000, propylene glycol,sodium oleate, glyceryl behenate, glyceryl palmitostearate, glycerylbenzoate, magnesium or sodium lauryl sulfate, and the like.

Suitable diluents for use in the solid dosage forms described hereininclude, but are not limited to, sugars (including lactose, sucrose, anddextrose), polysaccharides (including dextrates and maltodextrin),polyols (including mannitol, xylitol, and sorbitol), cyclodextrins andthe like.

Suitable wetting agents for use in the solid dosage forms describedherein include, for example, oleic acid, glyceryl monostearate, sorbitanmonooleate, sorbitan monolaurate, triethanolamine oleate,polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitanmonolaurate, quaternary ammonium compounds (e.g., Polyquat 10®), sodiumoleate, sodium lauryl sulfate, magnesium stearate, sodium docusate,triacetin, vitamin E TPGS and the like.

Suitable surfactants for use in the solid dosage forms described hereininclude, for example, sodium lauryl sulfate, sorbitan monooleate,polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bilesalts, glyceryl monostearate, copolymers of ethylene oxide and propyleneoxide, e.g., Pluronic® (BASF), and the like.

Suitable suspending agents for use in the solid dosage forms describedhere include, but are not limited to, polyvinylpyrrolidone, e.g.,polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidoneK25, or polyvinylpyrrolidone K30, polyethylene glycol, e.g., thepolyethylene glycol optionally is selected to have a molecular weight ofabout 300 to about 6000, or about 3350 to about 4000, or about 5400 toabout 7000, vinyl pyrrolidone/vinyl acetate copolymer (S630), sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,polysorbate-80, hydroxyethylcellulose, sodium alginate, gums, such as,e.g., gum tragacanth and gum acacia, guar gum, xanthans, includingxanthan gum, sugars, cellulosics, such as, e.g., sodiumcarboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose,hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80,sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylatedsorbitan monolaurate, povidone and the like.

Suitable antioxidants for use in the solid dosage forms described hereininclude, for example, e.g., butylated hydroxytoluene (BHT), sodiumascorbate, and tocopherol.

There is considerable overlap between additives used in the solid dosageforms described herein. Thus, the above-listed additives should be takenas merely exemplary, and not limiting, of the types of additives thatcan be included in solid dosage forms of the pharmaceutical compositionsdescribed herein.

In other embodiments, one or more layers of the pharmaceuticalformulation are plasticized. Illustratively, a plasticizer is generallya high boiling point solid or liquid. Suitable plasticizers can be addedfrom about 0.01% to about 50% by weight (w/w) of the coatingcomposition. Plasticizers include, but are not limited to, diethylphthalate, citrate esters, polyethylene glycol, glycerol, acetylatedglycerides, triacetin, polypropylene glycol, polyethylene glycol,triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, andcastor oil.

Compressed tablets are solid dosage forms prepared by compacting thebulk blend of the formulations described above. In various embodiments,compressed tablets which are designed to dissolve in the mouth willinclude one or more flavoring agents. In other embodiments, thecompressed tablets will include a film surrounding the final compressedtablet. In some embodiments, the film coating can provide a delayedrelease of the compounds of Formula (I) described herein from theformulation. In other embodiments, the film coating aids in patientcompliance (e.g., Opadry® coatings or sugar coating). Film coatingsincluding Opadry® typically range from about 1% to about 3% of thetablet weight. In other embodiments, the compressed tablets include oneor more excipients.

A capsule may be prepared, for example, by placing the bulk blend of theformulation of the compound described above, inside of a capsule. Insome embodiments, the formulations (non-aqueous suspensions andsolutions) are placed in a soft gelatin capsule. In other embodiments,the formulations are placed in standard gelatin capsules or non-gelatincapsules such as capsules comprising HPMC. In other embodiments, theformulation is placed in a sprinkle capsule, wherein the capsule may beswallowed whole or the capsule may be opened and the contents sprinkledon food prior to eating. In some embodiments, the therapeutic dose issplit into multiple (e.g., two, three, or four) capsules. In someembodiments, the entire dose of the formulation is delivered in acapsule form.

In various embodiments, the particles of the compound of Formula (I)described herein and one or more excipients are dry blended andcompressed into a mass, such as a tablet, having a hardness sufficientto provide a pharmaceutical composition that substantially disintegrateswithin less than about 30 minutes, less than about 35 minutes, less thanabout 40 minutes, less than about 45 minutes, less than about 50minutes, less than about 55 minutes, or less than about 60 minutes,after oral administration, thereby releasing the formulation into thegastrointestinal fluid.

In another aspect, dosage forms may include microencapsulatedformulations. In some embodiments, one or more other compatiblematerials are present in the microencapsulation material. Exemplarymaterials include, but are not limited to, pH modifiers, erosionfacilitators, anti-foaming agents, antioxidants, flavoring agents, andcarrier materials such as binders, suspending agents, disintegrationagents, filling agents, surfactants, solubilizers, stabilizers,lubricants, wetting agents, and diluents.

Microencapsulated compounds described herein may be formulated bymethods that include, e.g., spray drying processes, spinningdisk-solvent processes, hot melt processes, spray chilling methods,fluidized bed, electrostatic deposition, centrifugal extrusion,rotational suspension separation, polymerization at liquid-gas orsolid-gas interface, pressure extrusion, or spraying solvent extractionbath. In addition to these, several chemical techniques, e.g., complexcoacervation, solvent evaporation, polymer-polymer incompatibility,interfacial polymerization in liquid media, in situ polymerization,in-liquid drying, and desolvation in liquid media could also be used.Furthermore, other methods such as roller compaction,extrusion/spheronization, coacervation, or nanoparticle coating may alsobe used.

The pharmaceutical solid oral dosage forms including formulationsdescribed herein, which include a compound described herein, can befurther formulated to provide a controlled release of the compound ofFormula (I). Controlled release refers to the release of the compoundsdescribed herein from a dosage form in which it is incorporatedaccording to a desired profile over an extended period of time.Controlled release profiles include, for example, sustained release,prolonged release, pulsatile release, and delayed release profiles. Incontrast to immediate release compositions, controlled releasecompositions allow delivery of an agent to a subject over an extendedperiod of time according to a predetermined profile. Such release ratescan provide therapeutically effective levels of agent for an extendedperiod of time and thereby provide a longer period of pharmacologicresponse while minimizing side effects as compared to conventional rapidrelease dosage forms. Such longer periods of response provide for manyinherent benefits that are not achieved with the corresponding shortacting, immediate release preparations.

In other embodiments, the formulations described herein, which include acompound of Formula (I) described herein, are delivered using apulsatile dosage form. A pulsatile dosage form is capable of providingone or more immediate release pulses at predetermined time points aftera controlled lag time or at specific sites. Pulsatile dosage forms maybe administered using a variety of pulsatile formulations including, butare not limited to, those described in U.S. Pat. Nos. 5,011,692;5,017,381; 5,229,135; 5,840,329; 4,871,549; 5,260,068; 5,260,069;5,508,040; 5,567,441 and 5,837,284.

Many other types of controlled release systems are suitable for use withthe formulations described herein. Examples of such delivery systemsinclude, e.g., polymer-based systems, such as polylactic andpolyglycolic acid, polyanhydrides and polycaprolactone; porous matrices,nonpolymer-based systems that are lipids, including sterols, such ascholesterol, cholesterol esters and fatty acids, or neutral fats, suchas mono-, di- and triglycerides; hydrogel release systems; silasticsystems; peptide-based systems; wax coatings, bioerodible dosage forms,compressed tablets using conventional binders and the like. See, e.g.,Liberman et al., Pharmaceutical Dosage Forms, 2 Ed., Vol. 1, pp. 209-214(1990); Singh et al., Encyclopedia of Pharmaceutical Technology, 2ndEd., pp. 751-753 (2002); U.S. Pat. Nos. 4,327,725; 4,624,848; 4,968,509;5,461,140; 5,456,923; 5,516,527; 5,622,721; 5,686,105; 5,700,410;5,977,175; 6,465,014; and 6,932,983.

In some embodiments, pharmaceutical formulations are provided thatinclude particles of the compounds described herein, e.g. compounds ofFormula (I), and at least one dispersing agent or suspending agent fororal administration to a subject. The formulations may be a powderand/or granules for suspension, and upon admixture with water, asubstantially uniform suspension is obtained.

Liquid formulation dosage forms for oral administration can be aqueoussuspensions selected from the group including, but not limited to,pharmaceutically acceptable aqueous oral dispersions, emulsions,solutions, elixirs, gels, and syrups. See, e.g., Singh et al.,Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp. 754-757 (2002).

The aqueous suspensions and dispersions described herein can remain in ahomogenous state, as defined in The USP Pharmacists' Pharmacopeia (2005edition, chapter 905), for at least 4 hours. The homogeneity should bedetermined by a sampling method consistent with regard to determininghomogeneity of the entire composition. In one embodiment, an aqueoussuspension can be re-suspended into a homogenous suspension by physicalagitation lasting less than 1 minute. In another embodiment, an aqueoussuspension can be re-suspended into a homogenous suspension by physicalagitation lasting less than 45 seconds. In yet another embodiment, anaqueous suspension can be re-suspended into a homogenous suspension byphysical agitation lasting less than 30 seconds. In still anotherembodiment, no agitation is necessary to maintain a homogeneous aqueousdispersion.

The pharmaceutical compositions described herein may include sweeteningagents such as, but not limited to, acacia syrup, acesulfame K, alitame,anise, apple, aspartame, banana, Bavarian cream, berry, black currant,butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream,chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream,cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate,cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger,glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey,isomalt, lemon, lime, lemon cream, monoammonium glyrrhizinate(MagnaSweet®), maltol, mannitol, maple, marshmallow, menthol, mintcream, mixed berry, neohesperidine DC, neotame, orange, pear, peach,peppermint, peppermint cream, Prosweet® Powder, raspberry, root beer,rum, saccharin, safrole, sorbitol, spearmint, spearmint cream,strawberry, strawberry cream, stevia, sucralose, sucrose, sodiumsaccharin, saccharin, aspartame, acesulfame potassium, mannitol, talin,sucralose, sorbitol, swiss cream, tagatose, tangerine, thaumatin, tuttifruitti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol,or any combination of these flavoring ingredients, e.g., anise-menthol,cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint,honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream,vanilla-mint, and mixtures thereof.

For intravenous injections, compounds described herein may be formulatedin aqueous solutions, preferably in physiologically compatible bufferssuch as Hank's solution, Ringer's solution, or physiological salinebuffer. For transmucosal administration, penetrants appropriate to thebarrier to be permeated are used in the formulation. Such penetrants aregenerally recognized in the field. For other parenteral injections,appropriate formulations may include aqueous or nonaqueous solutions,preferably with physiologically compatible buffers or excipients. Suchexcipients are generally recognized in the field.

Parenteral injections may involve bolus injection or continuousinfusion. Formulations for injection may be presented in unit dosageform, e.g., in ampoules or in multi-dose containers, with an addedpreservative. The pharmaceutical composition described herein may be ina form suitable for parenteral injection as a sterile suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilizing and/or dispersingagents. Pharmaceutical formulations for parenteral administrationinclude aqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active compounds may be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. Aqueousinjection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use.

In certain embodiments, delivery systems for pharmaceutical compoundsmay be employed, such as, for example, liposomes and emulsions. Incertain embodiments, compositions provided herein also include anmucoadhesive polymer, selected from among, for example,carboxymethylcellulose, carbomer (acrylic acid polymer),poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylicacid/butyl acrylate copolymer, sodium alginate and dextran.

Generally, an agent, such as a compound of Formula (I), is administeredin an amount effective for amelioration of, or prevention of thedevelopment of symptoms of, the disease or disorder (i.e., atherapeutically effective amount). Thus, a therapeutically effectiveamount can be an amount that is capable of at least partially preventingor reversing a disease or disorder. The dose required to obtain aneffective amount may vary depending on the agent, formulation, diseaseor disorder, and individual to whom the agent is administered.

Determination of effective amounts may also involve in vitro assays inwhich varying doses of agent are administered to cells in culture andthe concentration of agent effective for ameliorating some or allsymptoms is determined in order to calculate the concentration requiredin vivo. Effective amounts may also be based in in vivo animal studies.

An agent can be administered prior to, concurrently with and subsequentto the appearance of symptoms of a disease or disorder. In someembodiments, an agent is administered to a subject with a family historyof the disease or disorder, or who has a phenotype that may indicate apredisposition to a disease or disorder, or who has a genotype whichpredisposes the subject to the disease or disorder.

Methods of Dosing and Treatment Regimens

The compositions containing the compound(s) described herein can beadministered for prophylactic and/or therapeutic treatments. Intherapeutic applications, the compositions are administered to a patientalready suffering from a disease or condition, in an amount sufficientto cure or at least partially arrest the symptoms of the disease orcondition. Amounts effective for this use will depend on the severityand course of the disease or condition, previous therapy, the patient'shealth status, weight, and response to the drugs, and the judgment ofthe treating physician.

In prophylactic applications, compositions containing the compoundsdescribed herein are administered to a patient susceptible to orotherwise at risk of a particular disease, disorder or condition. Suchan amount is defined to be a “prophylactically effective amount ordose.” In this use, the precise amounts also depend on the patient'sstate of health, weight, and the like. When used in a patient, effectiveamounts for this use will depend on the severity and course of thedisease, disorder or condition, previous therapy, the patient's healthstatus and response to the drugs, and the judgment of the treatingphysician.

In the case wherein the patient's condition does not improve, upon thedoctor's discretion the administration of the compounds may beadministered chronically, that is, for an extended period of time,including throughout the duration of the patient's life in order toameliorate or otherwise control or limit the symptoms of the patient'sdisease or condition.

In the case wherein the patient's status does improve, upon the doctor'sdiscretion the administration of the compounds may be givencontinuously; alternatively, the dose of drug being administered may betemporarily reduced or temporarily suspended for a certain length oftime (i.e., a “drug holiday”). The length of the drug holiday can varybetween 2 days and 1 year, including by way of example only, 2 days, 3days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days,180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or365 days. The dose reduction during a drug holiday may be from about 10%to about 100%, including, by way of example only, about 10%, about 15%,about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%,about 85%, about 90%, about 95%, or about 100%.

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, the dosage or thefrequency of administration, or both, can be reduced, as a function ofthe symptoms, to a level at which the improved disease, disorder orcondition is retained. Patients can, however, require intermittenttreatment on a long-term basis upon any recurrence of symptoms.

The amount of a given agent that will correspond to such an amount willvary depending upon factors such as the particular compound, disease orcondition and its severity, the identity (e.g., weight) of the subjector host in need of treatment, but can nevertheless be determined in amanner recognized in the field according to the particular circumstancessurrounding the case, including, e.g., the specific agent beingadministered, the route of administration, the condition being treated,and the subject or host being treated. In general, however, dosesemployed for adult human treatment will typically be in the range ofabout 0.02-about 5000 mg per day, in some embodiments, about 1-about1500 mg per day. The desired dose may conveniently be presented in asingle dose or as divided doses administered simultaneously (or over ashort period of time) or at appropriate intervals, for example as two,three, four or more sub-doses per day.

The pharmaceutical composition described herein may be in unit dosageforms suitable for single administration of precise dosages. In unitdosage form, the formulation is divided into unit doses containingappropriate quantities of one or more compound. The unit dosage may bein the form of a package containing discrete quantities of theformulation. Non-limiting examples are packaged tablets or capsules, andpowders in vials or ampoules. Aqueous suspension compositions can bepackaged in single-dose non-reclosable containers. Alternatively,multiple-dose reclosable containers can be used, in which case it istypical to include a preservative in the composition. By way of exampleonly, formulations for parenteral injection may be presented in unitdosage form, which include, but are not limited to ampoules, or inmulti-dose containers, with an added preservative.

The daily dosages appropriate for the compounds described herein arefrom about 0.01 mg/kg to about 20 mg/kg. In one embodiment, the dailydosages are from about 0.1 mg/kg to about 10 mg/kg. An indicated dailydosage in the larger mammal, including, but not limited to, humans, isin the range from about 0.5 mg to about 1000 mg, convenientlyadministered in a single dose or in divided doses, including, but notlimited to, up to four times a day or in extended release form. Suitableunit dosage forms for oral administration include from about 1 to about500 mg active ingredient. In one embodiment, the unit dosage is about 1mg, about 5 mg, about, 10 mg, about 20 mg, about 50 mg, about 100 mg,about 200 mg, about 250 mg, about 400 mg, or about 500 mg. The foregoingranges are merely suggestive, as the number of variables in regard to anindividual treatment regime is large, and considerable excursions fromthese recommended values are not uncommon. Such dosages may be altereddepending on a number of variables, not limited to the activity of thecompound used, the disease or condition to be treated, the mode ofadministration, the requirements of the individual subject, the severityof the disease or condition being treated, and the judgment of thepractitioner.

Toxicity and therapeutic efficacy of such therapeutic regimens can bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, including, but not limited to, the determinationof the LD₅₀ (the dose lethal to 50% of the population) and the ED₅₀ (thedose therapeutically effective in 50% of the population). The dose ratiobetween the toxic and therapeutic effects is the therapeutic index andit can be expressed as the ratio between LD₅₀ and ED₅₀. Compoundsexhibiting high therapeutic indices are preferred. The data obtainedfrom cell culture assays and animal studies can be used in formulating arange of dosage for use in human. The dosage of such compounds liespreferably within a range of circulating concentrations that include theED₅₀ with minimal toxicity. The dosage may vary within this rangedepending upon the dosage form employed and the route of administrationutilized.

Combination Treatments

The compounds of Formula (I)-(VII) described herein, and compositionsthereof, may also be used in combination with other therapeutic agentsthat are selected for their therapeutic value for the condition to betreated. In general, the compositions described herein and, inembodiments where combinational therapy is employed, other agents do nothave to be administered in the same pharmaceutical composition, and may,because of different physical and chemical characteristics, have to beadministered by different routes. The determination of the mode ofadministration and the advisability of administration, where possible,in the same pharmaceutical composition, is well within the knowledge ofthe clinician. The initial administration can be made according toestablished protocols recognized in the field, and then, based upon theobserved effects, the dosage, modes of administration and times ofadministration can be modified by the clinician.

In certain instances, it may be appropriate to administer at least onecompound described herein in combination with another therapeutic agent.By way of example only, if one of the side effects experienced by apatient upon receiving one of the compounds herein, such as a compoundof Formula (I), is nausea, then it may be appropriate to administer ananti-nausea agent in combination with the initial therapeutic agent. Or,by way of example only, the therapeutic effectiveness of one of thecompounds described herein may be enhanced by administration of anadjuvant (i.e., by itself the adjuvant may have minimal therapeuticbenefit, but in combination with another therapeutic agent, the overalltherapeutic benefit to the patient is enhanced). Or, by way of exampleonly, the benefit experienced by a patient may be increased byadministering one of the compounds described herein with anothertherapeutic agent (which also includes a therapeutic regimen) that alsohas therapeutic benefit. In any case, regardless of the disease,disorder or condition being treated, the overall benefit experienced bythe patient may simply be additive of the two therapeutic agents or thepatient may experience a synergistic benefit.

In some embodiments, a compound of Formula (I)-(VII) is administered incombination with an aminoglycoside antibiotic. In some embodiments, acompound of Formula (I)-(VII) is administered in combination with anaminoglycoside antibiotic selected from streptomycin, neomycin,framycetin, paromomycin, paromomycin sulfate, ribostamycin, kanamycin,amikacin, arbekacin, bekanamycin, dibekacin, tobramycin, spectinomycin,hygromycin B, gentamicin, netilmicin, sisomicin, isepamicin, verdamicin,and astromicin. In some embodiments, a compound of Formula (I)-(VII) isadministered in combination with streptomycin. In some embodiments, acompound of Formula (I)-(VII) is administered in combination withamikacin. In some embodiments, a compound of Formula (I)-(VII) isadministered in combination with neomycin. In some embodiments, acompound of Formula (I)-(VII) is administered in combination withkanamycin. In some embodiments, a compound of Formula (I)-(VII) isadministered in combination with gentamicin. In some embodiments, acompound of Formula (I)-(VII) is administered in combination withtobramycin.

In some embodiments, a compound of Formula (I)-(VII) is administered incombination with a chemotherapeutic agent. In some embodiments, acompound of Formula (I)-(VII) is administered in combination with achemotherapeutic agent selected from cisplatin and carboplatin. In someembodiments, a compound of Formula (I)-(VII) is administered incombination with cisplatin. In some embodiments, a compound of Formula(I)-(VII) is administered in combination with carboplatin.

The particular choice of compounds used will depend upon the diagnosisof the attending physicians and their judgment of the condition of thepatient and the appropriate treatment protocol. The compounds may beadministered concurrently (e.g., simultaneously, essentiallysimultaneously or within the same treatment protocol) or sequentially,depending upon the nature of the disease, disorder, or condition, thecondition of the patient, and the actual choice of compounds used. Thedetermination of the order of administration, and the number ofrepetitions of administration of each therapeutic agent during atreatment protocol, is well within the knowledge of the physician afterevaluation of the disease being treated and the condition of thepatient.

Therapeutically-effective dosages can vary when the drugs are used intreatment combinations. Methods for experimentally determiningtherapeutically-effective dosages of drugs and other agents for use incombination treatment regimens are described in the literature. Forexample, the use of metronomic dosing, i.e., providing more frequent,lower doses in order to minimize toxic side effects, has been describedextensively in the literature Combination treatment further includesperiodic treatments that start and stop at various times to assist withthe clinical management of the patient.

For combination therapies described herein, dosages of theco-administered compounds will of course vary depending on the type ofco-drug employed, on the specific drug employed, on the disease orcondition being treated and so forth. In addition, when co-administeredwith one or more biologically active agents, the compound providedherein may be administered either simultaneously with the biologicallyactive agent(s), or sequentially. If administered sequentially, theattending physician will decide on the appropriate sequence ofadministering protein in combination with the biologically activeagent(s).

In any case, the multiple therapeutic agents (one of which is a compoundof Formula (I)-(VII) described herein) may be administered in any orderor even simultaneously. If simultaneously, the multiple therapeuticagents may be provided in a single, unified form, or in multiple forms(by way of example only, either as a single pill or as two separatepills). One of the therapeutic agents may be given in multiple doses, orboth may be given as multiple doses. If not simultaneous, the timingbetween the multiple doses may vary from more than zero weeks to lessthan four weeks. In addition, the combination methods, compositions andformulations are not to be limited to the use of only two agents; theuse of multiple therapeutic combinations are also envisioned.

It is understood that the dosage regimen to treat, prevent, orameliorate the condition(s) for which relief is sought, can be modifiedin accordance with a variety of factors. These factors include thedisorder or condition from which the subject suffers, as well as theage, weight, sex, diet, and medical condition of the subject. Thus, thedosage regimen actually employed can vary widely and therefore candeviate from the dosage regimens set forth herein.

The pharmaceutical agents which make up the combination therapydisclosed herein may be a combined dosage form or in separate dosageforms intended for substantially simultaneous administration. Thepharmaceutical agents that make up the combination therapy may also beadministered sequentially, with either therapeutic compound beingadministered by a regimen calling for two-step administration. Thetwo-step administration regimen may call for sequential administrationof the active agents or spaced-apart administration of the separateactive agents. The time period between the multiple administration stepsmay range from, a few minutes to several hours, depending upon theproperties of each pharmaceutical agent, such as potency, solubility,bioavailability, plasma half-life and kinetic profile of thepharmaceutical agent. Circadian variation of the target moleculeconcentration may also determine the optimal dose interval.

In addition, the compounds described herein also may be used incombination with procedures that may provide additional or synergisticbenefit to the patient. By way of example only, patients are expected tofind therapeutic and/or prophylactic benefit in the methods describedherein, wherein pharmaceutical composition of a compound disclosedherein and/or combinations with other therapeutics are combined withgenetic testing to determine whether that individual is a carrier of amutant gene that is known to be correlated with certain diseases orconditions.

The compounds described herein and combination therapies can beadministered before, during or after the occurrence of a disease orcondition, and the timing of administering the composition containing acompound can vary. Thus, for example, the compounds can be used as aprophylactic and can be administered continuously to subjects with apropensity to develop conditions or diseases in order to prevent theoccurrence of the disease or condition. The compounds and compositionscan be administered to a subject during or as soon as possible after theonset of the symptoms. The administration of the compounds can beinitiated within the first 48 hours of the onset of the symptoms,preferably within the first 48 hours of the onset of the symptoms, morepreferably within the first 6 hours of the onset of the symptoms, andmost preferably within 3 hours of the onset of the symptoms. The initialadministration can be via any route practical, such as, for example, anintravenous injection, a bolus injection, infusion over about 5 minutesto about 5 hours, a pill, a capsule, transdermal patch, buccal delivery,and the like, or combination thereof. A compound is preferablyadministered as soon as is practicable after the onset of a disease orcondition is detected or suspected, and for a length of time necessaryfor the treatment of the disease, such as, for example, from 1 day toabout 3 months. The length of treatment can vary for each subject, andthe length can be determined using the known criteria. For example, thecompound or a formulation containing the compound can be administeredfor at least 2 weeks, preferably about 1 month to about 5 years.

EXAMPLES

Unless otherwise noted, reagents and solvents were used as received fromcommercial suppliers. Anhydrous solvents and oven-dried glassware wereused for synthetic transformations sensitive to moisture and/or oxygen.Yields were not optimized. Reaction times are approximate and were notoptimized. Column chromatography and thin layer chromatography (TLC)were performed on silica gel unless otherwise noted. Spectra are givenin ppm (δ) and coupling constants, J are reported in Hertz. For protonspectra the solvent peak was used as the reference peak.

Example 1: Preparation of2-[3-(4-chlorophenyl)ureido]-6-(cyclopropylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride (A6)

Step 1: tert-Butyl2-amino-3-carbamoyl-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate(A2)

A suspension of cyanoacetamide (4.65 g, 55.3 mmol), tert-butyl4-oxopiperidine-1-carboxylate (A1, 10.0 g, 50.3 mmol), sulfur (1.92 g,59.9 mmol), and morpholine (8.71 mL, 100 mmol) in ethanol (50 mL) washeated to reflux for 4 h and then cooled to room temperature. Thereaction mixture was concentrated under reduced pressure. The resultingresidue was triturated with a 1:1 mixture of methylene chloride andethyl acetate to afford compound A2 as a light orange solid (14.2 g,95%): ¹H NMR (300 MHz, DMSO-d₆) δ 6.98 (bs, 2H), 6.60 (bs, 2H), 4.27(bs, 2H), 3.55-3.48 (m, 2H), 2.71-2.67 (m, 2H), 1.42 (s, 9H). MS (M+H)298.

Step 2: tert-Butyl3-carbamoyl-2-[3-(4-chlorophenyl)ureido]-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate(A3)

A solution of 4-chlorophenyl isocyanate (11.1 g, 72.3 mmol), compound A2(19.5 g, 65.6 mmol), and triethylamine (12.0 mL, 86.1 mmol) in anhydroustetrahydrofuran (150 mL) was stirred at room temperature for 16 h. Afterthis time, the reaction mixture was concentrated under reduced pressure.The resulting residue was triturated with a mixture of 1:1 methylenechloride and ethyl acetate to afford compound A3 as an off-white solid(25.3 g, 86%): ¹H NMR (300 MHz, DMSO-d₆) δ 10.85 (s, 1H), 10.20 (s, 1H),7.52-7.45 (m, 3H), 7.34 (d, J=9.0 Hz, 2H), 6.94 (bs, 1H), 4.43 (s, 2H),3.57-3.53 (m, 2H), 2.79-2.75 (m, 2H), 1.43 (s, 9H). MS (M+Na) 473.

Step 3:2-[3-(4-Chlorophenyl)ureido]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidetrifluoroacetate (A4)

To a solution of compound A3 (16.0 g, 35.5 mmol) in methylene chloride(100 mL) was added trifluoroacetic acid (30.0 mL, 392 mmol) dropwiseover 5 min at 0° C. After the addition complete, the reaction mixturewas warmed to room temperature and stirred for 4 h. The reaction mixturewas concentrated under reduced pressure and the resulting residue wastriturated with ethyl acetate (75 mL) to afford compound A4 as anoff-white solid (16.5 g, quantitative yield): ¹H NMR (500 MHz, DMSO-d₆)δ 10.97 (s, 1H), 10.24 (s, 1H), 9.17 (bs, 2H), 7.60-7.12 (m, 6H), 4.25(s, 2H), 3.37-3.34 (m, 2H), 3.01-2.98 (m, 2H). MS (M+H) 351.

Step 4:2-[3-(4-Chlorophenyl)ureido]-6-(cyclopropylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide(A5)

To a slurry of compound A4 (300 mg, 0.645 mmol) in methanol (4 mL) andtetrahydrofuran (2 mL) two drops of glacial acetic acid andcyclopropanecarbaldehyde (94.0 mg, 1.34 mmol) were added. After stirringat room temperature for 5 min, sodium cyanoborohydride (122 mg, 1.94mmol) was added and the reaction mixture was stirred for an additional 3h. After this time, the reaction was quenched with water (25 mL) andsaturated aqueous sodium bicarbonate (50 mL). The resulting mixture wasextracted with ethyl acetate (100 mL). The extracts were dried overanhydrous sodium sulfate, filtered, and concentrated under reducedpressure. The resulting residue was triturated with methylene chlorideto afford compound A5 as a white solid (245 mg, 94%): ¹H NMR (500 MHz,DMSO-d₆) δ 10.95 (s, 1H), 10.16 (s, 1H), 7.54-7.40 (m, 3H), 7.33 (d,J=9.0 Hz, 2H), 6.83 (bs, 1H), 3.54 (s, 2H), 2.84-2.78 (m, 2H), 2.78-2.69(m, 2H), 2.36 (s, 2H), 0.95-0.87 (m, 1H), 0.53-0.45 (m, 2H), 0.17-0.09(m, 2H). MS (M+H) 405.

Step 5:2-[3-(4-Chlorophenyl)ureido]-6-(cyclopropylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride (A6)

To a solution of compound A5 (121 mg, 0.299 mmol) in tetrahydrofuran (5mL) was added hydrochloride (2 M in diethyl ether, 0.200 mL, 0.400mmol). After stirring at room temperature for 15 min, the reactionmixture was concentrated under reduced pressure and the resultingresidue was triturated with methylene chloride to afford compound A6 asa yellow solid (94 mg, 71%): ¹H NMR (500 MHz, DMSO-d₆) δ 10.97 (s, 1H),10.28 (bs, 1H), 10.26 (s, 1H), 7.55-7.48 (m, 3H), 7.35 (d, J=9.0 Hz,2H), 7.14 (bs, 1H), 4.61-4.57 (m, 1H), 4.31-4.28 (m, 1H), 3.72-3.70 (m,1H), 3.39-3.36 (m, 1H), 3.22-3.19 (m, 1H), 3.11-3.08 (m, 3H), 1.19-1.11(m, 1H), 0.70-0.63 (m, 2H), 0.45-0.39 (m, 2H). MS (M+H) 405.

Example 2: Preparation of2-[3-(4-Chlorophenyl)ureido]-6-isopropyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 1. MS (M+H) 393. ¹H NMR (500 MHz, DMSO-d₆) δ 11.03 (s, 1H),10.28 (s, 1H), 10.25 (bs, 1H), 7.55-7.02 (m, 6H), 4.43-4.39 (m, 1H),4.36-4.28 (m, 1H), 3.71-3.61 (m, 2H), 3.30-3.04 (m, 3H), 1.36-1.32 (m,6H).

Example 3: Preparation of2-[3-(4-Chlorophenyl)ureido]-6-(3-methoxypropyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 1. MS (M+H) 423. ¹H NMR (500 MHz, DMSO-d₆) δ 10.95 (s, 1H),10.30 (bs, 1H), 10.26 (s, 1H), 7.70-7.00 (m, 6H), 4.57-4.53 (m, 1H),4.26-4.22 (m, 1H), 3.71-3.62 (m, 1H), 3.48-3.40 (m, 2H), 3.28-3.20 (m,6H), 3.13-3.06 (m, 2H), 2.04-1.96 (m, 2H).

Example 4: Preparation of tert-Butyl3-{3-carbamoyl-2-[3-(4-chlorophenyl)ureido]-4,5-dihydrothieno[2,3-c]pyridin-6(7H)-yl}pyrrolidine-1-carboxylate

The title compound was prepared using a similar procedure as describedin Example 1. MS (M+H) 520. ¹H NMR (500 MHz, DMSO-d₆) δ 10.94 (s, 1H),10.16 (s, 1H), 7.71-7.20 (m, 5H), 6.82 (bs, 1H), 3.62-3.56 (m, 2H),3.53-3.49 (m, 1H), 3.42-3.37 (m, 1H), 3.27-3.15 (m, 1H), 3.18-2.97 (m,2H), 2.83-2.66 (m, 4H), 2.14-2.08 (m, 1H), 1.80-1.70 (m, 1H), 1.41 (s,9H).

Example 5: Preparation of2-[3-(4-Chlorophenyl)ureido]-6-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 1. MS (M+H) 435. ¹H NMR (500 MHz, DMSO-d₆) δ 11.00 (s, 1H),10.41 (bs, 1H), 10.27 (s, 1H), 7.72-7.30 (m, 5H), 7.11 (bs, 1H),4.51-4.47 (m, 1H), 4.39-4.33 (m, 1H), 4.04-3.96 (m, 2H), 3.81-3.75 (m,1H), 3.59-3.51 (m, 1H), 3.40-3.35 (m, 2H), 3.32-3.28 (m, 1H), 3.17-3.09(m, 2H), 2.12-2.09 (m, 1H), 2.07-1.98 (m, 1H), 1.83-1.72 (m, 2H).

Example 6: Preparation of2-[3-(4-Chlorophenyl)ureido]-6-(oxetan-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 1. MS (M+H) 407. ¹H NMR (500 MHz, DMSO-d₆) δ 11.61 (bs, 1H),10.93 (s, 1H), 10.26 (s, 1H), 7.73-6.97 (m, 6H), 4.93-4.70 (m, 3H),4.69-4.49 (m, 2H), 4.19-4.06 (m, 1H), 3.78-3.48 (m, 2H), 3.40-3.21 (m,1H), 3.19-3.02 (m, 2H).

Example 7: Preparation of(+/−)-2-[3-(4-Chlorophenyl)ureido]-6-(pyrrolidin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidedihydrochloride

The title compound was prepared using a similar procedure as describedin Example 1. MS (M+H) 420. ¹H NMR (500 MHz, DMSO-d₆) δ 11.85 (bs, 1H),10.96 (s, 1H), 10.26 (s, 1H), 9.48 (bs, 2H), 7.73-7.00 (m, 6H),4.70-4.50 (m, 1H), 4.42-4.28 (m, 1H), 4.22-4.00 (m, 1H), 3.86-3.40 (m,5H), 3.31-3.00 (m, 4H), 2.45-2.27 (m, 1H).

Example 8: Preparation of2-[3-(4-Chlorophenyl)ureido]-6-(1-methylpiperidin-4-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidedihydrochloride

The title compound was prepared using a similar procedure as describedin Example 1. MS (M+H) 448. ¹H NMR (500 MHz, DMSO-d₆) δ 11.15 (bs, 1H),10.99 (s, 1H), 10.49 (bs, 1H), 10.28 (s, 1H), 7.79-6.98 (m, 6H),4.58-4.49 (m, 1H), 4.42-4.34 (m, 1H), 3.78-3.48 (m, 4H), 3.21-3.10 (m,2H), 3.18-2.94 (m, 2H), 2.83-2.72 (m, 4H), 2.48-2.30 (m, 2H), 2.19-2.05(m, 2H).

Example 9: Preparation of(+/−)-2-[3-(4-Chlorophenyl)ureido]-6-(1-methylpyrrolidin-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidedihydrochloride

The title compound was prepared using a similar procedure as describedin Example 1. MS (M+H) 434. ¹H NMR (500 MHz, DMSO-d₆) δ 11.14 (bs, 1H),10.97 (s, 1H), 10.77 (bs, 1H), 10.25 (s, 1H), 7.74-6.83 (m, 6H),4.85-3.89 (m, 4H), 3.82-3.50 (m, 3H), 3.21-3.00 (m, 2H), 2.96-2.82 (m,4H), 2.62-2.50 (m, 3H).

Example 10: Preparation of tert-Butyl2-{3-carbamoyl-2-[3-(4-chlorophenyl)ureido]-4,5-dihydrothieno[2,3-c]pyridin-6(7H)-yl}ethylcarbamate

The title compound was prepared using a similar procedure as describedin Example 1. MS (M+H) 494. ¹H NMR (300 MHz, DMSO-d₆) δ 10.97 (s, 1H),10.19 (s, 1H), 7.67-7.26 (m, 5H), 6.85 (bs, 1H), 6.79-6.68 (m, 1H),3.57-3.48 (m, 2H), 3.18-3.03 (m, 2H), 2.83-2.63 (m, 4H), 2.60-2.50 (m,2H), 1.38 (s, 9H).

Example 11: Preparation of6-(2-Aminoethyl)-2-[3-(4-chlorophenyl)ureido]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidedihydrochloride

The title compound was prepared using a similar procedure as describedin Example 1. MS (M+H) 394. ¹H NMR (500 MHz, DMSO-d₆) δ 11.37 (bs, 1H),10.96 (s, 1H), 10.27 (s, 1H), 8.34 (bs, 3H), 7.70-6.94 (m, 6H),4.72-4.56 (m, 1H), 4.38-4.23 (m, 1H), 3.80-3.69 (m, 1H), 3.59-3.39 (m,5H), 3.23-3.10 (m, 2H).

Example 12: Preparation of2-[3-(4-Chlorophenyl)ureido]-6-(cyclobutylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 1. MS (M+H) 419. ¹H NMR (500 MHz, DMSO-d₆) δ 10.95 (s, 1H),10.34 (bs, 1H), 10.26 (s, 1H), 7.77-6.94 (m, 6H), 4.47-4.38 (m, 1H),4.23-4.11 (m, 1H), 3.65-3.54 (m, 1H), 3.31-3.21 (m, 3H), 3.13-3.04 (m,2H), 2.87-2.78 (m, 1H), 2.19-2.07 (m, 2H), 1.95-1.78 (m, 4H).

Example 13: Preparation of4-{3-Carbamoyl-2-[3-(4-chlorophenyl)ureido]-4,5-dihydrothieno[2,3-c]pyridin-6(7H)-yl}butanoicacid hydrochloride

The title compound was prepared using a similar procedure as describedin Example 1. MS (M+H) 437. ¹H NMR (500 MHz, DMSO-d₆) δ 12.24 (bs, 1H),10.95 (s, 1H), 10.25 (s, 1H), 7.77-6.90 (m, 6H), 4.40-4.08 (m, 2H),3.48-3.35 (m, 2H), 3.18-2.98 (m, 4H), 2.38-2.33 (m, 2H), 1.97-1.88 (m,2H).

Example 14: Preparation of tert-Butyl4-{3-carbamoyl-2-[3-(4-chlorophenyl)ureido]-4,5-dihydrothieno[2,3-c]pyridin-6(7H)-yl}butanoate

The title compound was prepared using a similar procedure as describedin Example 1. MS (M+H) 493. ¹H NMR (300 MHz, DMSO-d₆) δ 10.96 (s, 1H),10.18 (s, 1H), 7.63-6.70 (m, 6H), 3.52-3.41 (m, 2H), 2.85-2.72 (m, 2H),2.71-2.61 (m, 2H), 2.50-2.40 (m, 2H), 2.29-2.19 (m, 2H), 1.81-1.67 (m,2H), 1.39 (s, 9H).

Example 15: Preparation of6-(2-Acetamidoethyl)-2-[3-(4-chlorophenyl)ureido]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidetrifluoroacetate

The title compound was prepared using a similar procedure as describedin Example 1. MS (M+H) 436. ¹H NMR (500 MHz, DMSO-d₆) δ 10.97 (s, 1H),10.25 (s, 1H), 9.88 (bs, 1H), 8.12 (bs, 1H), 7.70-7.02 (m, 6H),4.63-4.58 (m, 1H), 4.31-4.26 (m, 1H), 3.77-3.73 (m, 1H), 3.62-3.41 (m,4H), 3.38-3.22 (m, 1H), 3.16-3.07 (m, 2H), 1.86 (s, 3H).

Example 16: Preparation of2-[3-(4-Chlorophenyl)ureido]-6-(cyclohexylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 1. MS (M+H) 447. ¹H NMR (500 MHz, DMSO-d₆) δ 10.94 (s, 1H),10.27 (s, 1H), 10.15 (bs, 1H), 7.70-7.00 (m, 6H), 4.58-4.53 (m, 1H),4.25-4.22 (m, 1H), 3.66-3.59 (m, 1H), 3.43-3.31 (m, 1H), 3.12-3.00 (m,4H), 1.90-1.60 (m, 6H), 1.33-1.11 (m, 3H), 1.02-0.92 (m, 2H).

Example 17: Preparation of2-[3-(4-Chlorophenyl)ureido]-6-(cyclopentylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 1. MS (M+H) 433. ¹H NMR (500 MHz, DMSO-d₆) δ 10.95 (s, 1H),10.27 (s, 1H), 10.14 (bs, 1H), 7.73-6.98 (m, 6H), 4.57-4.53 (m, 1H),4.30-4.22 (m, 1H), 3.70-3.61 (m, 1H), 3.33-3.07 (m, 5H), 2.38-2.27 (m,1H), 1.91-1.83 (m, 2H), 1.68-1.52 (m, 4H), 1.32-1.20 (m, 2H).

Example 18: Preparation of tert-Butyl6-{3-carbamoyl-2-[3-(4-chlorophenyl)ureido]-4,5-dihydrothieno[2,3-c]pyridin-6(7H)-yl}hexanoate

The title compound was prepared using a similar procedure as describedin Example 1. MS (M+H) 521. ¹H NMR (500 MHz, DMSO-d₆) δ 10.95 (s, 1H),10.19 (s, 1H), 7.70-7.30 (m, 5H), 6.89 (bs, 1H), 3.68-3.40 (m, 3H),2.93-2.70 (m, 3H), 2.52-2.48 (m, 2H), 2.23-2.17 (m, 2H), 1.66-1.49 (m,4H), 1.40 (s, 9H), 1.35-1.28 (m, 2H).

Example 19: Preparation of tert-Butyl5-{3-carbamoyl-2-[3-(4-chlorophenyl)ureido]-4,5-dihydrothieno[2,3-c]pyridin-6(7H)-yl}pentanoate

The title compound was prepared using a similar procedure as describedin Example 1. MS (M+H) 507. ¹H NMR (500 MHz, DMSO-d₆) δ 10.94 (s, 1H),10.17 (s, 1H), 7.61-7.29 (m, 5H), 6.84 (bs, 1H), 3.50-3.40 (m, 2H),2.82-2.74 (m, 2H), 2.68-2.59 (m, 2H), 2.47-2.40 (m, 2H), 2.25-2.19 (m,2H), 1.57-1.48 (m, 4H), 1.40 (s, 9H).

Example 20: Preparation of Methyl4-{3-carbamoyl-2-[3-(4-chlorophenyl)ureido]-4,5-dihydrothieno[2,3-c]pyridin-6(7H)-yl}butanoatehydrochloride

The title compound was prepared using a similar procedure as describedin Example 1. MS (M+H) 451. ¹H NMR (500 MHz, DMSO-d₆) δ 10.96 (s, 1H),10.26 (bs, 2H), 7.72-6.90 (m, 6H), 4.59-4.53 (m, 1H), 4.27-4.18 (m, 1H),3.74-3.63 (m, 1H), 3.62 (s, 3H), 3.30-3.18 (m, 3H), 3.12-3.02 (m, 2H),2.48-2.41 (m, 2H), 2.00-1.92 (m, 2H).

Example 21: Preparation of Ethyl4-{3-carbamoyl-2-[3-(4-chlorophenyl)ureido]-4,5-dihydrothieno[2,3-c]pyridin-6(7H)-yl}butanoatehydrochloride

The title compound was prepared using a similar procedure as describedin Example 1. MS (M+H) 465. ¹H NMR (500 MHz, DMSO-d₆) δ 10.96 (s, 1H),10.26 (s, 1H), 10.24 (bs, 1H), 7.72-7.00 (m, 6H), 4.60-4.54 (m, 1H),4.27-4.20 (m, 1H), 4.11-4.05 (m, 2H), 3.71-3.64 (m, 1H), 3.31-3.18 (m,3H), 3.11-3.02 (m, 2H), 2.48-2.41 (m, 2H), 2.01-1.92 (m, 2H), 1.20 (t,J=7.0 Hz, 3H).

Example 22: Preparation of tert-Butyl3-{3-carbamoyl-2-[3-(4-chlorophenyl)ureido]-4,5-dihydrothieno[2,3-c]pyridin-6(7H)-yl}cyclobutanecarboxylate

The title compound was prepared using a similar procedure as describedin Example 1. MS (M+H) 505. ¹H NMR (500 MHz, DMSO-d₆) δ 10.94 (s, 1H),10.16 (s, 1H), 7.72-7.19 (m, 5H), 6.82 (bs, 1H), 3.63-3.40 (m, 4H),2.93-2.70 (m, 4H), 2.37-2.22 (m, 2H), 2.03-1.87 (m, 2H), 1.40 (s, 9H).

Example 23: Preparation of2-[3-(4-Chlorophenyl)ureido]-6-[4-(dimethylamino)-4-oxobutyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 1. MS (M+H) 464. ¹H NMR (500 MHz, DMSO-d₆) δ 10.95 (s, 1H),10.53 (bs, 1H), 10.27 (s, 1H), 7.71-7.00 (m, 6H), 4.58-4.52 (m, 1H),4.26-4.18 (m, 1H), 3.69-3.63 (m, 1H), 3.34-3.30 (m, 1H), 3.28-3.05 (m,4H), 2.96 (s, 3H), 2.84 (s, 3H), 2.49-2.42 (m, 2H), 2.00-1.91 (m, 2H).

Example 24: Preparation of2-[3-(4-Chlorophenyl)ureido]-6-[(1-methylcyclobutyl)methyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidetrifluoroacetate

The title compound was prepared using a similar procedure as describedin Example 1. MS (M+H) 433. ¹H NMR (500 MHz, DMSO-d₆) δ 10.96 (s, 1H),10.25 (s, 1H), 9.71 (bs, 1H), 7.70-6.99 (m, 6H), 4.44-4.39 (m, 1H),4.29-4.22 (m, 1H), 3.61-3.48 (m, 1H), 3.43-3.32 (m, 1H), 3.31-3.23 (m,2H), 3.14-3.07 (m, 2H), 2.08-1.97 (m, 3H), 1.87-1.71 (m, 3H), 1.33 (s,3H).

Example 25: Preparation of2-[3-(4-Chlorophenyl)ureido]-6-[4-(isopropylamino)-4-oxobutyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 1. MS (M+H) 478. ¹H NMR (500 MHz, DMSO-d₆) δ 10.95 (s, 1H),10.52 (bs, 1H), 10.27 (s, 1H), 7.88-7.86 (m, 1H), 7.71-7.00 (m, 6H),4.58-4.52 (m, 1H), 4.27-4.23 (m, 1H), 3.86-3.82 (m, 1H), 3.71-3.66 (m,1H), 3.39-3.30 (m, 1H), 3.26-3.07 (m, 4H), 2.21-2.17 (m, 2H), 1.99-1.91(m, 2H), 1.05 (d, J=6.5 Hz, 6H).

Example 26: Preparation of2-[3-(4-Chlorophenyl)ureido]-6-isobutyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 1. MS (M+H) 407. ¹H NMR (500 MHz, DMSO-d₆) δ 10.95 (s, 1H),10.27 (s, 1H), 9.98 (bs, 1H), 7.90-6.80 (m, 6H), 4.55-3.63 (m, 3H),3.20-3.00 (m, 4H), 2.63-2.15 (m, 2H), 1.00 (bs, 6H).

Example 27: Preparation of2-[3-(4-Chlorophenyl)ureido]-6-neopentyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 1. MS (M+H) 421. ¹H NMR (500 MHz, DMSO-d₆) δ 10.92 (s, 1H),10.27 (s, 1H), 9.85 (bs, 1H), 7.80-6.90 (m, 6H), 4.56-4.29 (m, 2H),3.57-3.42 (m, 2H), 3.24-2.97 (m, 4H), 1.10 (s, 9H).

Example 28: Preparation of2-[3-(4-Chlorophenyl)ureido]-5-ethyl-5,6-dihydro-4H-thieno[2,3-c]pyrrole-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 1. MS (M+H) 365. ¹H NMR (500 MHz, DMSO-d₆) δ 11.99 (s, 1H),11.27 (s, 1H), 10.39 (s, 1H), 7.70-6.80 (m, 6H), 4.88-4.38 (m, 4H),3.40-3.38 (m, 2H), 1.31 (t, J=7.1 Hz, 3H).

Example 29: Preparation of tert-Butyl4-[3-(3-carbamoyl-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)ureido]benzoate

The title compound was prepared using a similar procedure as describedin Example 1. MS (M+H) 445. ¹H NMR (500 MHz, DMSO-d₆) δ 11.01 (s, 1H),10.42 (s, 1H), 7.90-6.80 (m, 6H), 3.70-3.40 (m, 2H), 2.95-2.60 (m, 6H),1.53 (s, 9H), 1.13 (bs, 3H).

Example 30: Preparation of tert-Butyl2-{4-[3-(3-carbamoyl-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)ureido]phenyl}acetate

The title compound was prepared using a similar procedure as describedin Example 1. MS (M+H) 459. ¹H NMR (500 MHz, DMSO-d₆) δ 10.89 (s, 1H),10.06 (s, 1H), 7.70-6.80 (m, 6H), 2.47 (s, 2H), 3.35-2.60 (m, 8H), 1.39(s, 9H), 1.25 (bs, 3H).

Example 31: Preparation of Methyl4-[3-(3-carbamoyl-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)ureido]benzoatetrifluoroacetate

The title compound was prepared using a similar procedure as describedin Example 1. MS (M+H) 403. ¹H NMR (300 MHz, DMSO-d₆) δ 11.04 (s, 1H),10.56 (s, 1H), 10.10 (bs, 1H), 7.93-6.90 (m, 6H), 4.59-4.18 (m, 2H),3.82 (s, 3H), 3.75-3.10 (m, 6H), 1.30 (t, J=7.2 Hz, 3H).

Example 32: Preparation of4-[3-(3-Carbamoyl-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)ureido]benzoicacid trifluoroacetate

The title compound was prepared using a similar procedure as describedin Example 1. MS (M+H) 389. ¹H NMR (300 MHz, DMSO-d₆) δ 12.70 (bs, 1H),11.02 (s, 1H), 10.51 (s, 1H), 9.97 (bs, 1H), 7.90-6.90 (m, 6H),4.60-4.18 (m, 2H), 3.72-3.10 (m, 6H), 1.30 (t, J=7.2 Hz, 3H).

Example 33: Preparation of2-{4-[3-(3-Carbamoyl-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)ureido]phenyl}aceticacid trifluoroacetate

The title compound was prepared using a similar procedure as describedin Example 1. MS (M+H) 403. ¹H NMR (500 MHz, DMSO-d₆) δ 12.26 (bs, 1H),10.89 (s, 1H), 10.09 (s, 1H), 9.93 (bs, 1H), 7.80-6.90 (m, 6H),4.56-3.67 (m, 3H), 3.50 (s, 2H), 3.32-3.08 (m, 5H), 1.29 (t, J=7.2 Hz,3H). ¹H NMR (300 MHz, DMSO-d₆) δ 11.00 (s, 1H), 10.38 (s, 1H), 10.06(bs, 1H), 8.15 (s, 1H), 7.88-6.90 (m, 8H), 4.58-4.22 (m, 2H), 3.66-3.04(m, 6H), 2.19-2.14 (m, 1H), 1.03-0.98 (m, 6H).

Example 34: Preparation of6-Isobutyl-2-[3-(naphthalen-2-yl)ureido]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 1. MS (M+H) 423. ¹H NMR (300 MHz, DMSO-d₆) δ 11.00 (s, 1H),10.38 (s, 1H), 10.06 (bs, 1H), 8.15 (s, 1H), 7.88-6.90 (m, 8H),4.58-4.22 (m, 2H), 3.66-3.04 (m, 6H), 2.19-2.14 (m, 1H), 1.03-0.98 (m,6H).

Example 35: Preparation of6-(Cyclobutylmethyl)-2-[3-(naphthalen-2-yl)ureido]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 1. MS (M+H) 435. ¹H NMR (300 MHz, DMSO-d₆) δ 11.00 (s, 1H),10.43 (bs, 1H), 10.37 (s, 1H), 8.14 (s, 1H), 7.90-7.00 (m, 8H),4.56-4.15 (m, 2H), 3.70-2.75 (m, 7H), 2.20-1.85 (m, 6H).

Example 36: Preparation of2-[3-(Naphthalen-2-yl)ureido]-6-neopentyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 1. MS (M+H) 437. ¹H NMR (500 MHz, DMSO-d₆) δ 10.96 (s, 1H),10.36 (s, 1H), 9.95 (bs, 1H), 8.13 (s, 1H), 7.90-6.90 (m, 8H), 4.60-4.25(m, 2H), 3.60-2.95 (m, 6H), 1.11 (s, 9H).

Example 37: Preparation of6-(4-Hydroxybutyl)-2-[3-(naphthalen-2-yl)ureido]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 1. MS (M+H) 439. ¹H NMR (300 MHz, DMSO-d₆) δ 11.10 (bs, 1H),10.99 (s, 1H), 10.40 (s, 1H), 8.15 (s, 1H), 7.90-6.90 (m, 8H), 4.70-4.20(m, 3H), 3.65-3.00 (m, 8H), 1.85-1.46 (m, 4H).

Example 38: Preparation of Methyl3-{3-carbamoyl-2-[3-(4-chlorophenyl)ureido]-4,5-dihydrothieno[2,3-c]pyridin-6(7H)-yl}-2,2-dimethylpropanoatehydrochloride

The title compound was prepared using a similar procedure as describedin Example 1. MS (M+H) 465. ¹H NMR (300 MHz, DMSO-d₆) δ 10.95 (s, 1H),10.32 (bs, 2H), 7.85-6.90 (m, 6H), 4.52-4.30 (m, 2H), 3.70 (s, 3H),3.50-3.05 (m, 6H), 1.32 (s, 6H).

Example 39: Preparation of2-[3-(4-Chloronaphthalen-1-yl)ureido]-6-isobutyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 1. MS (M+H) 457. ¹H NMR (300 MHz, DMSO-d₆) δ 11.01 (s, 1H),10.14 (s, 1H), 10.03 (bs, 1H), 8.27 (dd, J=7.2 and 2.1 Hz, 1H), 8.22(dd, J=7.2 and 2.1 Hz, 1H), 7.87 (d, J=8.1 Hz, 1H), 7.78-6.90 (m, 5H),4.58-4.52 (m, 1H), 4.24 (dd, J=15.0 and 6.3 Hz, 1H), 3.68-3.57 (m, 1H),3.14-3.00 (m, 5H), 2.21-2.09 (m, 1H), 1.01 (d, J=6.3 Hz, 3H), 0.99 (d,J=6.3 Hz, 3H).

Example 40: Preparation of2-[3-(4-Chloronaphthalen-1-yl)ureido]-6-(cyclobutylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 1. MS (M+H) 469. ¹H NMR (500 MHz, DMSO-d₆) δ 11.00 (s, 1H),10.35 (bs, 1H), 10.11 (s, 1H), 8.27 (d, J=8.0 Hz, 1H), 8.21 (d, J=8.0Hz, 1H), 7.75 (d, J=6.5 Hz, 1H), 7.72-6.95 (m, 5H), 4.44-4.40 (m, 1H),4.20-4.17 (m, 1H), 3.41-3.10 (m, 4H), 3.08 (bs, 2H), 2.82-2.79 (m, 1H),2.16-2.06 (m, 2H), 1.93-1.78 (m, 4H).

Example 41: Preparation of2-[3-(4-Chloronaphthalen-1-yl)ureido]-6-neopentyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 1. MS (M+H) 471. ¹H NMR (300 MHz, DMSO-d₆) δ 10.98 (s, 1H),10.15 (s, 1H), 9.98 (bs, 1H), 8.30-8.19 (m, 2H), 7.87 (d, J=8.4 Hz, 1H),7.78-7.00 (m, 5H), 4.57-4.51 (m, 1H), 4.33-4.26 (m, 1H), 3.61-3.39 (m,2H), 3.29-2.96 (m, 4H), 1.10 (s, 9H).

Example 42: Preparation of2-[3-(4-Chlorophenyl)ureido]-6-(dimethylamino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 1. MS (M+H) 393. ¹H NMR (500 MHz, DMSO-d₆) δ 11.01 (s, 1H),10.75 (bs, 1H), 10.18 (s, 1H), 7.70-6.70 (m, 6H), 3.45 (bs, 1H),3.18-2.70 (m, 10H), 2.30-1.80 (m, 2H).

Example 43: Preparation of6-(Azetidin-1-yl)-2-[3-(4-chlorophenyl)ureido]-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 1. MS (M+H) 405. ¹H NMR (300 MHz, CD₃OD) δ 7.48-7.26 (m, 4H),4.20-3.55 (m, 5H), 3.15-1.75 (m, 8H).

Example 44: Preparation of2-[3-(4-chlorophenyl)ureido]-6-[2-(piperidin-1-yl)ethyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamideditrifluoroacetate (B2)

Step 1:6-(2-Chloroethyl)-2-[3-(4-chlorophenyl)ureido]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide(B1)

To a slurry of compound A4 (200 mg, 0.431 mmol) and magnesium sulfate (2g) in methanol (4 mL) and tetrahydrofuran (2 mL) was added two drops ofglacial acetic acid and 2-chloroacetaldehyde (45% in water, 0.340 mL,1.95 mmol). After stirring at room temperature for 5 min, sodiumcyanoborohydride (271 mg, 4.31 mmol) was added and the reaction mixturewas stirred for an additional 16 h at room temperature. After this time,the reaction was diluted with saturated aqueous sodium bicarbonate (100mL), sonicated, and filtered. The filter cake was washed with water (50mL) and triturated with methylene chloride to afford compound B1 as awhite solid (176 mg, 99%): ¹H NMR (300 MHz, DMSO-d₆) δ 10.94 (s, 1H),10.19 (s, 1H), 7.57-7.29 (m, 5H), 6.87 (bs, 1H), 3.76 (t, J=6.6 Hz, 2H),3.57 (s, 2H), 2.87-2.71 (m, 6H). MS (M+H) 413.

Step 2:2-[3-(4-Chlorophenyl)ureido]-6-[2-(piperidin-1-yl)ethyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamideditrifluoroacetate (B2)

A solution of compound B1 (130 mg, 0.315 mmol) and piperidine (800 mg,9.40 mmol) in 1,4-dioxane (2.5 mL) was heated to 80° C. for 16 h. Afterthis time, the reaction mixture was cooled to room temperature andconcentrated under reduced pressure. The resulting residue was purifiedby flash column chromatography on silica gel eluting with methylenechloride to methanol/methylene chloride (1:9). Further purification byreverse-phase semi-preparative HPLC, eluting with 0.05% TFA inacetonitrile/water (gradient from 10% to 100%, Phenomenex Luna column)afforded compound B2 as a yellow solid (67 mg, 46%): ¹H NMR (500 MHz,DMSO-d₆) δ 10.98 (s, 1H), 10.20 (s, 1H), 7.52-7.29 (m, 5H), 6.89 (bs,1H), 6.51 (bs, 1H), 3.51 (m, 4H), 3.32-3.11 (m, 6H), 3.00-2.73 (m, 4H),1.80-1.69 (m, 4H), 1.58-1.48 (m, 2H). MS (M+H) 462.

Example 45: Preparation of2-[3-(4-Chlorophenyl)ureido]-6-[2-(4-methylpiperazin-1-yl)ethyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 44. MS (M+H) 477. ¹H NMR (500 MHz, DMSO-d₆) δ 10.95 (s, 1H),10.49 (bs, 1H), 10.27 (s, 1H), 7.70-6.97 (m, 6H), 4.42 (s, 2H),3.53-3.32 (m, 8H), 3.19-3.02 (m, 6H), 2.92-2.87 (m, 2H), 2.76 (s, 3H).

Example 46: Preparation of2-[3-(4-Chlorophenyl)ureido]-6-(2-morpholinoethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidetrifluoroacetate

The title compound was prepared using a similar procedure as describedin Example 44. MS (M+H) 464. ¹H NMR (500 MHz, DMSO-d₆) δ 11.28 (bs,0.5H), 10.66 (bs, 0.5H), 9.75 (bs, 0.5H), 8.85 (bs, 0.5H), 8.01 (bs,1H), 7.72-7.28 (m, 6H), 4.12-3.45 (m, 18H).

Example 47: Preparation of(+/−)-2-[3-(4-chlorophenyl)ureido]-6-(1-cyclobutylethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride [(+/−)-C2]

Step 1:(+/−)-2-[3-(4-Chlorophenyl)ureido]-6-(1-cyclobutylethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide[(+/−)-C1]

To a slurry of compound A4 (400 mg, 0.860 mmol), sodium acetate (212 mg,2.58 mmol), and magnesium sulfate (1 g) in anhydrousN,N-dimethylformamide (5 mL) was added 1-cyclobutylethanone (253 mg,2.57 mmol). After stirring at room temperature for 5 min, sodiumtriacetoxyborohydride (911 mg, 4.30 mmol) was added. The reactionmixture was then heated at 50° C. for 20 h. After this time, thereaction mixture was cooled to room temperature and diluted withsaturated aqueous sodium bicarbonate (10 mL), methanol (5 mL), methylenechloride (20 mL), and water (10 mL). The layers were separated and theaqueous layer back extracted with 20% methanol/methylene chloride (2×30mL). The combined organic layers were dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure. Theresulting residue was purified by flash column chromatography on silicagel eluting with 2% to 6% methanol/methylene chloride to afford compound(+/−)-C1 as a white solid (199 mg, 53%): MS (M+H) 433.

Step 2:(+/−)-2-[3-(4-Chlorophenyl)ureido]-6-(1-cyclobutylethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride [(+/−)-C2]

To a solution of compound (+/−)-C1 (36 mg, 0.083 mmol) in methanol (5mL) and methylene chloride (5 mL) was added hydrochloride (2 M indiethyl ether, 0.800 mL, 1.60 mmol). After stirring at room temperaturefor 15 min, the reaction mixture was concentrated under reduced pressureand the residue was triturated with a mixture of methanol (0.5 mL),ethyl acetate (5 mL), and hexanes (5 mL) to afford compound (+/−)-C2 asa light yellow solid (33 mg, 85%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.04(bs, 1H), 10.30 (s, 1H), 10.10 (bs, 1H), 7.80-7.00 (m, 6H), 4.34-4.27(m, 2H), 3.70-3.55 (m, 2H), 3.30-3.00 (m, 3H), 2.80-2.60 (m, 1H),2.20-1.60 (m, 6H), 1.22 (d, J=5.5 z, 3H). MS (M+H) 433.

Example 48: Preparation of(+/−)-2-[3-(4-Chlorophenyl)ureido]-6-(3-methylbutan-2-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 47. MS (M+H) 421. ¹H NMR (300 MHz, DMSO-d₆) δ 11.01 (s, 1H),10.31 (s, 1H), 9.99 and 9.91 (2 s, 1H), 7.80-6.90 (m, 6H), 4.50-3.60 (m,3H), 3.25-3.05 (m, 4H), 2.36-2.27 (m, 1H), 1.29-1.22 (m, 3H), 0.99-0.94(m, 6H).

Example 49: Preparation of6-[(3r,5r,7r)-Adamantan-1-ylmethyl]-2-[3-(4-chlorophenyl)ureido]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 47. MS (M+H) 499. ¹H NMR (500 MHz, DMSO-d₆) δ 10.86 (s, 1H),10.54 (bs, 1H), 10.35 (s, 1H), 7.80-7.00 (m, 6H), 4.51-4.21 (m, 2H),3.45-2.75 (m, 6H), 2.00-1.65 (m, 15H).

Example 50: Preparation of6-(3-amino-3-oxopropyl)-2-[3-(4-chlorophenyl)ureido]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride (D2)

Step 1:6-(3-Amino-3-oxopropyl)-2-[3-(4-chlorophenyl)ureido]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide(D1)

A solution of compound A4 (200 mg, 0.431 mmol), acrylamide (156 mg, 2.19mmol), and diisopropylethylamine (0.400 mL, 2.25 mmol) inN,N-dimethylformamide (2.5 mL) was heated at 50° C. for 8 h. After thistime, the reaction mixture was cooled to room temperature andconcentrated under reduced pressure. The resulting residue was purifiedby flash column chromatography on silica gel eluting with 0% to 10%methanol/methylene chloride to afford compound D1 as a yellow solid (180mg, 99%): ¹H NMR (300 MHz, DMSO-d₆) δ 10.95 (s, 1H), 10.19 (s, 1H),7.59-7.29 (m, 6H), 6.90-6.73 (m, 2H), 3.48 (s, 2H), 2.83-2.65 (m, 6H),2.33-2.25 (m, 2H). MS (M+H) 422.

Step 2:6-(3-Amino-3-oxopropyl)-2-[3-(4-chlorophenyl)ureido]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride (D2)

To a solution of compound D1 (90.0 mg, 0.210 mmol) in tetrahydrofuran(2.5 mL) and methanol (2.5 mL) was added hydrochloride (2 M in diethylether, 0.140 mL, 0.280 mmol). After stirring at room temperature for 30min, the reaction mixture was concentrated under reduced pressure andthe resulting residue was triturated with methylene chloride to affordcompound D2 as a yellow solid (95 mg, 99%): ¹H NMR (500 MHz, DMSO-d₆) δ10.94 (s, 1H), 10.55 (bs, 1H), 10.27 (s, 1H), 7.62 (bs, 1H), 7.55-7.30(m, 5H), 7.19-7.02 (m, 2H), 4.52-4.48 (m, 1H), 4.28-4.25 (m, 1H),3.68-3.60 (m, 1H), 3.49-3.42 (m, 3H), 3.13-3.08 (m, 2H), 2.74-2.67 (m,2H). MS (M+H) 422.

Example 51: Preparation of tert-Butyl3-{3-Carbamoyl-2-[3-(4-chlorophenyl)ureido]-4,5-dihydrothieno[2,3-c]pyridin-6(7H)-yl}propanoate

The title compound was prepared using a similar procedure as describedin Example 50. MS (M+H) 479. ¹H NMR (500 MHz, DMSO-d₆) δ 10.96 (s, 1H),10.16 (s, 1H), 7.62-7.28 (m, 5H), 6.83 (bs, 1H), 3.49 (s, 2H), 2.80-2.63(m, 6H), 2.47-2.41 (m, 2H), 1.40 (s, 9H).

Example 52: Preparation of3-{3-Carbamoyl-2-[3-(4-chlorophenyl)ureido]-4,5-dihydrothieno[2,3-c]pyridin-6(7H)-yl}propanoicacid trifluoroacetate

The title compound was prepared using a similar procedure as describedin Example 50. MS (M+H) 423. ¹H NMR (500 MHz, DMSO-d₆) δ 12.73 (bs, 1H),10.95 (s, 1H), 10.25 (s, 1H), 10.02 (bs, 1H), 7.70-6.94 (m, 6H),4.64-4.22 (m, 2H), 3.76-3.48 (m, 4H), 3.13-3.06 (m, 2H), 2.87-2.79 (m,2H).

Example 53: Preparation of2-[3-(4-Chlorophenyl)ureido]-6-[3-(dimethylamino)-3-oxopropyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 50. MS (M+H) 450. ¹H NMR (500 MHz, DMSO-d₆) δ 10.94 (s, 1H),10.26 (s, 1H), 10.17 (bs, 1H), 7.72-7.00 (m, 6H), 4.60-4.54 (m, 1H),4.32-4.26 (m, 1H), 3.77-3.67 (m, 1H), 3.51-3.35 (m, 3H), 3.12-3.02 (m,2H), 2.99 (s, 3H), 2.93-2.87 (m, 2H), 2.86 (s, 3H).

Example 54: Preparation of Isopropyl3-{3-carbamoyl-2-[3-(4-chlorophenyl)ureido]-4,5-dihydrothieno[2,3-c]pyridin-6(7H)-yl}propanoatehydrochloride

The title compound was prepared using a similar procedure as describedin Example 50. MS (M+H) 465. ¹H NMR (500 MHz, DMSO-d₆) δ 10.95 (s, 1H),10.46 (bs, 1H), 10.26 (s, 1H), 7.71-6.97 (m, 6H), 5.00-4.91 (m, 1H),4.57-4.51 (m, 1H), 4.30-4.25 (m, 1H), 3.75-3.67 (m, 1H), 3.56-3.38 (m,3H), 3.15-3.02 (m, 2H), 2.98-2.87 (m, 2H), 1.22 (d, J=6.0 Hz, 6H).

Example 55: Preparation of Methyl3-{3-carbamoyl-2-[3-(4-chlorophenyl)ureido]-4,5-dihydrothieno[2,3-c]pyridin-6(7H)-yl}propanoate

The title compound was prepared using a similar procedure as describedin Example 50. MS (M+H) 437. ¹H NMR (300 MHz, DMSO-d₆) δ 10.94 (s, 1H),10.19 (s, 1H), 7.68-7.28 (m, 5H), 6.85 (bs, 1H), 3.60 (s, 3H), 3.53-3.47(m, 2H), 2.80-2.66 (m, 6H), 2.61-2.53 (m, 2H).

Example 56: Preparation of Ethyl3-{3-carbamoyl-2-[3-(4-chlorophenyl)ureido]-4,5-dihydrothieno[2,3-c]pyridin-6(7H)-yl}propanoatehydrochloride

The title compound was prepared using a similar procedure as describedin Example 50. MS (M+H) 451. ¹H NMR (500 MHz, DMSO-d₆) δ 10.95 (s, 1H),10.49 (bs, 1H), 10.26 (s, 1H), 7.72-6.99 (m, 6H), 4.57-4.52 (m, 1H),4.30-4.25 (m, 1H), 4.13 (q, J=7.5 Hz, 2H), 3.76-3.66 (m, 1H), 3.57-3.37(m, 3H), 3.12-3.08 (m, 2H), 2.98-2.89 (m, 2H), 1.22 (t, J=7.0 Hz, 3H).

Example 57: Preparation of2-[3-(4-Chlorophenyl)ureido]-6-[3-(isopropylamino)-3-oxopropyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 50. MS (M+H) 464. ¹H NMR (500 MHz, DMSO-d₆) δ 10.94 (s, 1H),10.31 (bs, 1H), 10.26 (s, 1H), 8.07-8.03 (m, 1H), 7.69-7.00 (m, 6H),4.53-4.47 (m, 1H), 4.30-4.25 (m, 1H), 3.88-3.82 (m, 1H), 3.68-3.63 (m,1H), 3.51-3.35 (m, 3H), 3.12-3.08 (m, 2H), 2.67-2.63 (m, 2H), 1.07 (d,J=6.5 Hz, 6H).

Example 58: Preparation of tert-butyl2-{3-carbamoyl-2-[3-(4-chlorophenyl)ureido]-4,5-dihydrothieno[2,3-c]pyridin-6(7H)-yl}acetate(E1)

A solution of compound A4 (300 mg, 0.646 mmol), diisopropylethylamine(0.350 mL, 1.97 mmol), and tert-butyl 2-bromoacetate (0.140 mL, 0.950mmol) in tetrahydrofuran (4 mL) was stirred at room temperature for 8 h.After this time, the reaction mixture was diluted with methylenechloride (10 mL), sonicated, and filtered to afford compound E1 as alight yellow solid (191 mg, 64%): ¹H NMR (500 MHz, DMSO-d₆) δ 10.93 (s,1H), 10.18 (s, 1H), 7.59-7.29 (m, 5H), 6.89 (bs, 1H), 3.61 (s, 2H), 3.30(s, 2H), 2.82-2.76 (m, 4H), 1.43 (s, 9H). MS (M+H) 465.

Example 59: Preparation of (+/−)-tert-Butyl2-{3-carbamoyl-2-[3-(4-chlorophenyl)ureido]-4,5-dihydrothieno[2,3-c]pyridin-6(7H)-yl}propanoate

The title compound was prepared using a similar procedure as describedin Example 58. MS (M+H) 479. ¹H NMR (500 MHz, DMSO-d₆) δ 10.92 (s, 1H),10.16 (s, 1H), 7.58-7.28 (m, 5H), 6.83 (bs, 1H), 3.75-3.67 (m, 2H),3.44-3.36 (m, 1H), 2.91-2.87 (m, 1H), 2.81-2.73 (m, 3H), 1.43 (s, 9H),1.28-1.17 (m, 3H).

Example 60: Preparation of2-[3-(4-Chlorophenyl)ureido]-6-(2-hydroxyethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 58. MS (M+H) 395. ¹H NMR (500 MHz, DMSO-d₆) δ 10.95 (s, 1H),10.68 (bs, 1H), 10.29 (s, 1H), 7.70-6.99 (m, 6H), 5.46-5.35 (m, 1H),4.53-4.47 (m, 1H), 4.36-4.28 (m, 1H), 3.88-3.83 (m, 2H), 3.72-3.65 (m,1H), 3.63-3.59 (m, 1H), 3.47-3.36 (m, 1H), 3.13-3.08 (m, 2H), 1.76-1.74(m, 1H).

Example 61: Preparation of2-{3-Carbamoyl-2-[3-(4-chlorophenyl)ureido]-4,5-dihydrothieno[2,3-c]pyridin-6(7H)-yl}aceticacid hydrochloride

The title compound was prepared using a similar procedure as describedin Example 58. MS (M+H) 409. ¹H NMR (500 MHz, DMSO-d₆) δ 10.93 (s, 1H),10.22 (s, 1H), 7.70-6.90 (m, 6H), 4.24-4.09 (m, 2H), 3.99-3.80 (m, 2H),3.55-3.39 (m, 2H), 3.02-2.96 (m, 2H).

Example 62: Preparation of(+/−)-2-{3-Carbamoyl-2-[3-(4-chlorophenyl)ureido]-4,5-dihydrothieno[2,3-c]pyridin-6(7H)-yl}propanoicacid hydrochloride

The title compound was prepared using a similar procedure as describedin Example 58. MS (M+H) 423. ¹H NMR (500 MHz, DMSO-d₆) δ 10.97 (s, 1H),10.26 (s, 1H), 7.70-6.90 (m, 6H), 4.51-4.17 (m, 3H), 3.20-3.00 (m, 4H),1.60-1.52 (m, 3H).

Example 63: Preparation of2-[3-(4-Chlorophenyl)ureido]-6-[(1-methylcyclopropyl)methyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 58. MS (M+H) 419. ¹H NMR (500 MHz, DMSO-d₆) δ 10.97 (s, 1H),10.27 (s, 1H), 10.10 (bs, 1H), 7.71-6.99 (m, 6H), 4.58-4.53 (m, 1H),4.32-4.25 (m, 1H), 3.72-3.68 (m, 1H), 3.32-3.28 (m, 2H), 3.19-2.99 (m,3H), 1.20 (s, 3H), 0.68-0.47 (m, 4H).

Example 64: Preparation of2-[3-(4-chloro-3-methylphenyl)ureido]-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride (F6)

Step 1: 1-Chloro-4-isocyanato-2-methylbenzene (F2)

To the stirred mixture of 4-chloro-3-methylaniline (F1, 1.01 g, 7.13mmol) and triethylamine (866 mg, 8.56 mmol) in methylene chloride (20mL) at −20° C. under nitrogen was added phosgene solution (0.15weight/weight in toluene, 6.15 g, 9.13 mmol) dropwise over 5 min. Afteraddition, the reaction mixture was warmed up to room temperature over 2h, and then stirred at room temperature for another 2 h. After thistime, the reaction mixture was cooled to 0° C., and slowly quenched withsaturated aqueous sodium bicarbonate (30 mL). The mixture was extractedwith ethyl acetate (100 mL). The organic extract was washed with 2 Mhydrochloric acid (50 mL), brine (30 mL), dried over anhydrous sodiumsulfate, and filtered. The filtrate was concentrated under reducedpressure. The resulting residue was triturated with methylene chloride(40 mL) and filtered. The filtrate was concentrated under reducedpressure to provide compound F2 as a light brown liquid (1.08 g, 90%):¹H NMR (300 MHz, CDCl₃) δ 7.27 (d, J=8.4 Hz, 1H), 6.97 (d, J=2.4 Hz,1H), 6.88-6.84 (m, 1H), 2.34 (s, 3H).

Step 2:2-Amino-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide(F4)

A stirred mixture of compound F3 (22.7 g, 178 mmol), 2-cyanoacetamide(16.5 g, 197 mmol), sulphur (6.87 g, 215 mmol) and morpholine (31.5 g,362 mmol) in ethanol (350 mL) was heated to reflux under nitrogen for 5h. After this time, the reaction mixture was cooled to room temperatureand concentrated under reduced pressure. The residue was mixed withsaturated aqueous sodium bicarbonate (200 mL), water (200 mL). Theaqueous mixture was extracted with methylene chloride (5×200 mL). Thecombined organic extracts were dried over anhydrous sodium sulfate,filtered, and concentrated under reduced pressure. The resulting residuewas triturated with cold methanol (30 mL) and filtered. The filter cakewas washed with cold methanol (2×10 mL) and then dried under reducedpressure to provide compound F4 as a yellow solid (21.7 g, 54%): ¹H NMR(300 MHz, DMSO-d₆) δ 6.98 (s, 2H), 6.52 (bs, 2H), 3.29 (s, 2H), 2.66 (d,J=4.8 Hz, 2H), 2.60 (d, J=4.8 Hz, 2H), 2.46 (q, J=7.2 Hz, 2H), 1.04 (t,J=7.2 Hz, 3H). MS (M+H) 226.

Step 3:2-[3-(4-Chloro-3-methylphenyl)ureido]-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide(F5)

To a stirred solution of compound F4 (450 mg, 2.00 mmol) in anhydroustetrahydrofuran (10 mL) at room temperature under nitrogen was added asolution of compound F2 (402 mg, 2.40 mmol) in anhydrous methylenechloride (6 mL) dropwise over 3 min. Then the reaction mixture wasstirred overnight at room temperature. The reaction mixture wasfiltered. The filter cake was washed with methylene chloride (5 mL) andthen dried under reduced pressure to provide compound F5 as a whitesolid (301 mg, 38%): ¹H NMR (300 MHz, DMSO-d₆) δ 10.94 (s, 1H), 10.12(s, 1H), 7.48-6.75 (m, 5H), 3.45 (s, 2H), 2.77 (d, J=4.8 Hz, 2H), 2.65(d, J=4.8 Hz, 2H), 2.55-2.45 (m, 2H), 2.30 (s, 3H), 1.07 (t, J=6.6 Hz,3H).

Step 4:2-[3-(4-Chloro-3-methylphenyl)ureido]-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride (F6)

To a stirred mixture of compound F5 (157 mg, 0.400 mmol) in methylenechloride (50 mL) at room temperature was added hydrochloride (2 M indiethyl ether, 0.300 mL, 0.600 mmol). After addition, the mixture wasconcentrated under reduced pressure. The resulting solid was trituratedwith methylene chloride and filtered to afford compound F6 as yellowsolid: ¹H NMR (500 MHz, DMSO-d₆) δ 10.94 (s, 1H), 10.84 (bs, 1H), 10.22(s, 1H), 7.75-6.90 (m, 5H), 4.49 (d, J=14.5 Hz, 1H), 4.22-4.16 (m, 1H),3.65-3.62 (m, 1H), 3.38-3.05 (m, 5H), 2.30 (s, 3H), 1.32 (t, J=7.2 Hz,3H). MS (M+H) 393.

Example 65: Preparation of2-[3-(2-Chlorophenyl)ureido]-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 64. MS (M+H) 379. ¹H NMR (300 MHz, DMSO-d₆) δ 10.83 (s, 1H),10.60 (bs, 1H), 9.69 (s, 1H), 7.87 (d, J=6.9 Hz, 1H), 7.69-7.06 (m, 5H),4.53-4.48 (m, 1H), 4.23-4.15 (m, 1H), 3.67-3.62 (m, 1H), 3.36-3.10 (m,3H), 3.06 (bs, 2H), 1.31 (t, J=7.1 Hz, 3H).

Example 66: Preparation of6-Ethyl-2-[3-(4-fluorophenyl)ureido]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 64. MS (M+H) 363. ¹H NMR (300 MHz, DMSO-d₆) δ 10.93 (s, 1H),10.69 (bs, 1H), 10.19 (s, 1H), 7.80-6.89 (m, 6H), 4.54-4.48 (m, 1H),4.23-4.15 (m, 1H), 3.67-3.62 (m, 1H), 3.33-3.00 (m, 5H), 1.31 (t, J=7.2Hz, 3H).

Example 67: Preparation of2-[3-(4-Cyanophenyl)ureido]-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 64. MS (M+H) 370. ¹H NMR (300 MHz, DMSO-d₆) δ 11.08 (s, 1H),10.77 (bs, 1H), 10.68 (s, 1H), 8.00-6.95 (m, 6H), 4.55-4.49 (m, 1H),4.22-4.15 (m, 1H), 3.70-3.56 (m, 1H), 3.40-3.04 (m, 5H), 1.32 (t, J=6.8Hz, 3H).

Example 68: Preparation of2-(3-Cyclohexylureido)-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 64. MS (M+H) 351. ¹H NMR (300 MHz, DMSO-d₆) δ 10.48-10.33 (m,2H), 7.71-6.85 (m, 3H), 4.50-4.44 (m, 1H), 4.19-4.15 (m, 1H), 3.70-3.61(m, 1H), 3.50-2.95 (m, 6H), 1.80-1.05 (m, 13H).

Example 69: Preparation of6-Ethyl-2-[3-(pyridin-3-yl)ureido]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidedihydrochloride

The title compound was prepared using a similar procedure as describedin Example 64. MS (M+H) 346. ¹H NMR (300 MHz, DMSO-d₆) δ 11.26 (s, 1H),11.04 (s, 1H), 10.95 (bs, 1H), 8.98 (s, 1H), 8.48 (d, J=5.4 Hz, 1H),8.27 (d, J=8.4 Hz, 1H), 7.82 (dd, J=8.4 and 5.4 Hz, 1H), 7.81-7.00 (m,2H), 4.55-4.17 (m, 3H), 3.71-3.60 (m, 1H), 3.39-3.05 (m, 4H), 1.32 (t,J=7.2 Hz, 3H).

Example 70: Preparation of2-[3-(3,4-Difluorophenyl)ureido]-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 64. MS (M+H) 381. ¹H NMR (300 MHz, DMSO-d₆) δ 11.01 (s, 1H),10.76 (bs, 1H), 10.41 (s, 1H), 7.85-6.88 (m, 5H), 4.54-4.46 (m, 1H),4.29-4.14 (m, 1H), 3.69-3.61 (m, 1H), 3.39-3.00 (m, 5H), 1.32 (t, J=7.1Hz, 3H).

Example 71: Preparation of6-Ethyl-2-[3-(3-fluorophenyl)ureido]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 64. MS (M+H) 363. ¹H NMR (300 MHz, DMSO-d₆) δ 10.98 (s, 1H),10.41 (bs, 1H), 10.39 (s, 1H), 7.80-6.75 (m, 6H), 4.56-4.47 (m, 1H),4.25-4.16 (m, 1H), 3.68-3.62 (m, 1H), 3.49-3.00 (m, 5H), 1.31 (t, J=7.2Hz, 3H).

Example 72: Preparation of6-Ethyl-2-[3-(4-(trifluoromethyl)phenyl)ureido]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 64. MS (M+H) 413. ¹H NMR (300 MHz, DMSO-d₆) δ 11.04 (s, 1H),10.85 (bs, 1H), 10.60 (s, 1H), 8.15-6.90 (m, 6H), 4.60-4.46 (m, 1H),4.26-4.15 (m, 1H), 3.67-3.60 (m, 1H), 3.49-3.00 (m, 5H), 1.32 (t, J=7.2Hz, 3H).

Example 73: Preparation of2-[3-(3-Cyanophenyl)ureido]-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 64. MS (M+H) 370. ¹H NMR (300 MHz, DMSO-d₆) δ 11.06 (s, 1H),10.78 (bs, 1H), 10.56 (s, 1H), 7.99 (s, 1H), 7.88-6.85 (m, 5H),4.55-4.46 (m, 1H), 4.25-4.15 (m, 1H), 3.68-3.62 (m, 1H), 3.32-3.00 (m,5H), 1.32 (t, J=7.2 Hz, 3H).

Example 74: Preparation of2-[3-(2,3-Dichlorophenyl)ureido]-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 64. MS (M+H) 413. ¹H NMR (300 MHz, DMSO-d₆) δ 10.88 (s, 1H),10.59 (bs, 1H), 9.84 (s, 1H), 7.88 (dd, J=7.8 and 1.8 Hz, 1H), 7.75-7.15(m, 4H), 4.54-4.48 (m, 1H), 4.24-4.15 (m, 1H), 3.68-3.62 (m, 1H),3.34-3.13 (m, 3H), 3.06 (bs, 2H), 1.31 (t, J=7.2 Hz, 3H).

Example 75: Preparation of2-[3-(3-Chlorobenzyl)ureido]-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 64. MS (M+H) 393. ¹H NMR (300 MHz, DMSO-d₆) δ 10.70 (s,1H),10.57 (bs, 1H), 8.30 (t, J=5.2 Hz, 1H), 7.70-6.91 (m, 6H), 4.51-4.42(m, 1H), 4.30 (d, J=5.2 Hz, 2H), 4.19-4.11 (m, 1H), 3.66-3.60 (m, 1H),3.32-3.11 (m, 3H), 3.06 (bs, 2H), 1.30 (t, J=6.8 Hz, 3H).

Example 76: Preparation of2-[3-(4-Chlorobenzyl)ureido]-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 64. MS (M+H) 393. ¹H NMR (300 MHz, DMSO-d₆) δ 10.68 (s, 1H),10.62 (bs, 1H), 8.29 (t, J=5.4 Hz, 1H), 7.69-6.90 (m, 6H), 4.49-4.42 (m,1H), 4.28 (d, J=5.4 Hz, 2H), 4.17-4.10 (m, 1H), 3.68-3.60 (m, 1H),3.31-3.00 (m, 5H), 1.30 (t, J=7.1 Hz, 3H).

Example 77: Preparation of2-[3-(5-Chloropyridin-3-yl)ureido]-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidedihydrochloride

The title compound was prepared using a similar procedure as describedin Example 64. MS (M+H) 380. ¹H NMR (300 MHz, DMSO-d₆) δ 11.15 (s, 1H),10.74 (bs, 1H), 10.68 (s, 1H), 8.51 (d, J=2.1 Hz, 1H), 8.29 (d, J=2.1Hz, 1H), 8.16 (t, J=2.1 Hz, 1H), 7.60 (bs, 1H), 7.20 (bs, 1H), 4.56-4.50(m, 1H), 4.23-4.15 (m, 1H), 3.80-3.61 (m, 2H), 3.35-3.00 (m, 4H), 1.32(t, J=7.2 Hz, 3H).

Example 78: Preparation of6-Ethyl-2-[3-(quinolin-3-yl)ureido]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidedihydrochloride

The title compound was prepared using a similar procedure as describedin Example 64. MS (M+H) 396. ¹H NMR (300 MHz, DMSO-d₆) δ 11.23 (s, 1H),10.89 (s, 1H), 10.78 (bs, 1H), 8.99 (s, 1H), 8.73 (s, 1H), 8.52-7.10 (m,6H), 4.55-4.50 (m, 1H), 4.26-3.90 (m, 2H), 3.69-3.63 (m, 1H), 3.35-3.08(m, 4H), 1.33 (t, J=7.2 Hz, 3H).

Example 79: Preparation of6-Ethyl-2-[3-(quinolin-6-yl)ureido]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidedihydrochloride

The title compound was prepared using a similar procedure as describedin Example 64. MS (M+H) 396. ¹H NMR (300 MHz, DMSO-d₆) δ 11.13 (bs 2H),10.93 (s, 1H), 9.08 (d, J=4.5 Hz, 1H), 9.02 (d, J=8.4 Hz, 1H), 8.56 (s,1H), 8.35 (d, J=9.3 Hz, 1H), 8.04-7.91 (m, 2H), 7.55 (bs, 1H), 7.20 (bs,1H), 4.55-4.48 (m, 1H), 4.32-3.00 (m, 7H), 1.35 (t, J=7.1 Hz, 1H).

Example 80: Preparation of2-[3-(Benzo[c][1,2,5]thiadiazol-4-yl)ureido]-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 64. MS (M+H) 403. ¹H NMR (300 MHz, DMSO-d₆) δ 10.95 (s, 1H),10.81 (s, 1H), 10.51 (bs, 1H), 8.24 (dd, J=5.7 and 2.7 Hz, 1H),7.73-7.25 (m, 4H), 4.57-4.50 (m, 1H), 4.25-4.15 (m, 1H), 3.69-3.62 (m,1H), 3.34-3.10 (m, 3H), 3.06 (bs, 2H), 1.32 (t, J=7.1 Hz, 3H).

Example 81: Preparation of6-Ethyl-2-[3-(isoquinolin-4-yl)ureido]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidedihydrochloride

The title compound was prepared using a similar procedure as describedin Example 64. MS (M+H) 396. ¹H NMR (300 MHz, DMSO-d₆) δ 11.19 (s, 1H),10.80 (bs, 1H), 10.70 (s, 1H), 9.50 (s, 1H), 9.13 (s, 1H), 8.56 (d,J=7.5 Hz, 1H), 8.47 (d, J=7.5 Hz, 1H), 8.19 (t, J=7.5 Hz, 1H), 8.00 (t,J=7.5 Hz, 1H), 7.64 (bs, 1H), 7.28 (bs, 1H), 4.57-4.50 (m, 1H),4.26-4.14 (m, 1H), 4.10-3.00 (m, 6H), 1.33 (t, J=7.2 Hz, 3H).

Example 82: Preparation of6-Ethyl-2-[3-(1-methyl-1H-indol-3-yl)ureido]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 64. MS (M+H) 398. ¹H NMR (300 MHz, DMSO-d₆) δ 10.90 (bs, 1H),10.42 (bs, 1H), 10.02 (bs, 1H), 7.71-6.95 (m, 7H), 4.54-4.49 (m, 1H),4.23-4.13 (m, 1H), 3.76 (s, 3H), 3.69-3.63 (m, 1H), 3.45-3.12 (m, 3H),3.09 (bs, 2H), 1.31 (t, J=7.2 Hz, 3H).

Example 83: Preparation of2-[3-(3-Chloro-4-methylphenyl)ureido]-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 64. MS (M+H) 393. ¹H NMR (300 MHz, DMSO-d₆) δ 10.96 (s, 1H),10.73 (bs, 1H), 10.25 (s, 1H), 7.67 (s, 1H), 7.65-6.90 (m, 4H),4.52-4.48 (m, 1H), 4.22-4.16 (m, 1H), 3.66-3.62 (m, 1H), 3.30-3.06 (m,5H), 2.27 (s, 3H), 1.33 (t, J=7.1 Hz, 3H).

Example 84: Preparation of6-Ethyl-2-[3-(1-methyl-1H-indol-4-yl)ureido]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 64. MS (M+H) 398. ¹H NMR (300 MHz, DMSO-d₆) δ 10.78 (s, 1H),10.69 (s, 1H), 9.83 (s, 1H), 7.61 (d, J=6.3 Hz, 1H), 7.60-7.10 (m, 5H),6.68 (d, J=3.0 Hz, 1H), 4.54-4.48 (m, 1H), 4.24-4.15 (m, 1H), 3.77 (s,3H), 3.70-3.62 (m, 1H), 3.29-3.10 (m, 3H), 3.08 (bs, 2H), 1.32 (t, J=7.2Hz, 3H).

Example 85: Preparation of2-[3-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)ureido]-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 64. MS (M+H) 425. ¹H NMR (300 MHz, DMSO-d₆) δ 11.00 (s, 1H),10.61 (bs, 1H), 10.38 (s, 1H), 7.65 (d, J=2.1 Hz, 1H), 7.64-6.95 (m,4H), 4.55-4.48 (m, 1H), 4.24-4.15 (m, 1H), 3.68-3.63 (m, 1H), 3.35-3.15(m, 3H), 3.10 (bs, 2H), 1.31 (t, J=7.2 Hz, 3H).

Example 86: Preparation of2-[3-(4-Chlorophenyl)ureido]-4-methyl-5-(morpholinomethyl)thiophene-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 64. MS (M+H) 407. ¹H NMR (300 MHz, DMSO-d₆) δ 10.65 (s, 1H),10.43 (bs, 1H), 10.25 (s, 1H), 7.64 (bs, 1H), 7.50 (d, J=8.7 Hz, 2H),7.35 (d, J=8.7 Hz, 2H), 7.34 (bs, 1H), 4.46 (s, 2H), 4.00-3.94 (m, 2H),3.73 (t, J=11.7 Hz, 2H), 3.36-3.22 (m, 2H), 3.16-3.05 (m, 2H), 2.36 (s,3H).

Example 87: Preparation of1-(4-Chlorophenyl)-3-(3-cyano-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)urea

The title compound was prepared using a similar procedure as describedin Example 64. MS (M+H) 361. ¹H NMR (500 MHz, DMSO-d₆) δ 10.19 (s, 1H),9.32 (s, 1H), 7.48 (d, J=9.0 Hz, 2H), 7.36 (d, J=9.0 Hz, 2H), 3.49-3.43(m, 2H), 2.77-2.69 (m, 2H), 2.59-2.53 (m, 4H), 1.07 (t, J=7.0 Hz, 3H).

Example 88: Preparation of2-[3-(4-Benzoylphenyl)ureido]-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide

The title compound was prepared using a similar procedure as describedin Example 64. MS (M+H) 449. ¹H NMR (500 MHz, DMSO-d₆) δ 11.05 (s, 1H),10.50 (s, 1H), 7.79-7.63 (m, 7H), 7.58-7.35 (m, 3H), 6.86 (bs, 1H), 3.47(s, 2H), 2.81-2.77 (m, 2H), 2.68-2.61 (m, 2H), 2.57-2.53 (m, 2H), 1.08(t, J=7.0 Hz, 3H).

Example 89: Preparation of2-[3-(4-Chlorophenyl)ureido]-6-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide

The title compound was prepared using a similar procedure as describedin Example 64. MS (M+H) 433. ¹H NMR (500 MHz, DMSO-d₆) δ 10.90 (s, 1H),10.17 (s, 1H), 7.71-7.29 (m, 5H), 6.87 (bs, 1H), 3.75 (s, 2H), 3.40-3.33(m, 2H), 2.92-2.88 (m, 2H), 2.82-2.78 (m, 2H).

Example 90: Preparation of2-[3-(4-Chlorophenyl)ureido]-5,5,7,7-tetramethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 64. MS (M+H) 407. ¹H NMR (300 MHz, DMSO-d₆) δ 10.80 (s, 1H),10.27 (s, 1H), 9.38 (bs, 2H), 7.80-6.90 (m, 6H), 2.92 (s, 2H), 1.73 (s,6H), 1.44 (s, 6H).

Example 91: Preparation of2-[3-(4-Chlorophenyl)ureido]-6-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide

The title compound was prepared using a similar procedure as describedin Example 64. MS (M+H) 364. ¹H NMR (300 MHz, DMSO-d₆) δ 10.68 (s, 1H),10.17 (s, 1H), 7.80-6.80 (m, 6H), 3.51 (s, 2H), 3.10-3.06 (m, 2H),2.60-2.55 (m, 2H).

Example 92: Preparation of2-[3-(4-Chlorophenyl)ureido]-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide

The title compound was prepared using a similar procedure as describedin Example 64. MS (M+H) 374. ¹H NMR (300 MHz, DMSO-d₆) δ 10.95 (s, 1H),10.21 (s, 1H), 7.70-6.70 (m, 6H), 4.62 (s, 2H), 3.85-3.81 (m, 2H), 2.79(bs, 2H).

Example 93: Preparation of6-ethyl-2-[3-(6-fluoronaphthalen-2-yl)ureido]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride (G3)

Step 1:6-Ethyl-2-[3-(6-fluoronaphthalen-2-yl)ureido]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide(G2)

To a stirred mixture of 6-fluoro-2-naphthoic acid (G1, 0.951 g, 5.00mmol), triethylamine (0.759 g, 7.50 mmol) in anhydrous toluene (40 mL)was added diphenyl phosphorazidate (1.51 g, 5.50 mmol). After addition,the reaction mixture was heated at 80° C. for 2 h and then cooled toroom temperature. The resulting solution was added to another stirredsolution of compound F4 (1.13 g, 5.00 mmol) in anhydrous tetrahydrofuran(50 mL). After addition, the resulting mixture was heated at 80° C. foranother 2 h. After this time, the reaction mixture was cooled to roomtemperature, quenched with saturated aqueous sodium bicarbonate (60 mL),and extracted with ethyl acetate (3×100 mL). The combined organicextracts were dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure. The resulting residue was purifiedby flash column chromatography on silica gel eluting withmethanol/methylene chloride (15:85) to afford compound G2 as anoff-white solid (451 mg, 22%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.01 (s,1H), 10.27 (s, 1H), 8.19 (d, J=1.8 Hz, 1H), 7.91 (dd, J=10.8 and 5.7 Hz,1H), 7.84 (d, J=9.0 Hz, 1H), 7.64-6.70 (m, 5H), 3.47 (s, 2H), 2.78 (d,J=5.1 Hz, 2H), 2.66 (d, J=5.1 Hz, 2H), 2.55-2.49 (m, 2H), 1.08 (t, J=7.0Hz, 3H). MS (M+H) 413.

Step 2:6-Ethyl-2-[3-(6-fluoronaphthalen-2-yl)ureido]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride (G3)

To a mixture of compound G2 (124 mg, 0.300 mmol) in methylene chloride(8 mL) at room temperature was added hydrochloride (2 M in diethylether, 1.00 mL, 2.00 mmol). The resulting mixture was sonicated for 20min, and then concentrated under reduced pressure. The residue wastriturated with methylene chloride to afford compound G3 as an off-whitesolid (105 mg, 78%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.02 (s, 1H), 10.56(bs, 1H), 10.38 (s, 1H), 8.19 (d, J=1.8 Hz, 1H), 7.92 (dd, J=9.0 and 5.7Hz, 1H), 7.84 (d, J=9.0 Hz, 1H), 7.85-6.90 (m, 5H), 4.16 (bs, 2H),3.75-2.80 (m, 6H), 1.28 (t, J=7.0 Hz, 3H). MS (M+H) 413.

Example 94: Preparation of2-[3-(5-Chlorothiophen-2-yl)ureido]-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 93. MS (M+H) 385. ¹H NMR (300 MHz, DMSO-d₆) δ 11.40 (s, 1H),11.13 (s, 1H), 10.72 (bs, 1H), 7.48 (bs, 2H), 6.85 (d, J=3.9 Hz, 1H),6.37 (d, J=3.9 Hz, 1H), 4.55-4.47 (m, 1H), 4.24-4.16 (m, 1H), 3.67-3.61(m, 1H), 3.33-3.04 (m, 5H), 1.31 (t, J=7.1 Hz, 3H).

Example 95: Preparation of1-(4-chlorophenyl)-3-[6-ethyl-3-(morpholine-4-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl]ureahydrochloride (H7)

Step 1: Ethyl2-amino-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate(H1)

A solution of ethyl 2-cyanoacetate (4.87 g, 43.1 mmol),1-ethylpiperidin-4-one (F3, 5.00 g, 39.3 mmol), sulfur (1.50 g, 46.8mmol), and morpholine (6.80 mL, 78.1 mmol) in ethanol (30 mL) was heatedto reflux for 6 h and then the reaction mixture was cooled to roomtemperature, concentrated under reduced pressure. The resulting residuewas purified by flash column chromatography on silica gel eluting withmethylene chloride to methanol to methylene chloride (1:19). Furtherpurification by flash column chromatography on silica gel was requiredeluting from methylene chloride to ethyl acetate to afford compound H1as a light orange solid (9.77 g, 98%): ¹H NMR (300 MHz, CDCl₃) δ 5.95(bs, 2H), 4.26 (q, J=7.2 Hz, 2H), 3.42-3.41 (m, 2H), 2.88-2.80 (m, 2H),2.77-2.69 (m, 2H), 2.57 (q, J=7.2 Hz, 2H), 1.33 (t, J=7.2 Hz, 3H), 1.16(t, J=7.2 Hz, 3H).

Step 2: Ethyl2-(tert-butoxycarbonylamino)-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate(H2)

A solution of compound H1 (2.00 g, 7.86 mmol), di-tert-butyl dicarbonate(3.50 g, 16.0 mmol), and 4-dimethylaminopyridine (97.0 mg, 0.790 mmol)in anhydrous 1,4-dioxane (25 mL) was stirred at 75° C. for 3 h. Afterthis time, the reaction mixture was cooled to room temperature andconcentrated under reduced pressure. The resulting residue was dissolvedin chloroform (200 mL) and washed with water (200 mL). The aqueous layerwas back extracted with chloroform (3×100 mL). The combined organicswere dried over anhydrous sodium sulfate, filtered, and concentratedunder reduced pressure to afford compound H2 as an orange viscous oil(3.43 g, >100%) that was used in the next step without furtherpurification.

Step 3:2-(tert-Butoxycarbonylamino)-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylicacid (H3)

To a solution of compound H2 (3.43 g, crude) in ethanol (25 mL) andwater (12 mL) was added sodium hydroxide (1.28 g, 32.0 mmol). Thereaction mixture was heated to 70° C. for 1 h. After this time, thereaction mixture was cooled to room temperature and diluted with water(25 mL) and ethyl acetate (75 mL). The layers were separated. Theaqueous layer was neutralized with 0.5 M citric acid to pH 7. Theaqueous layer was then chilled to 0° C. for 16 h. After this time, theresulting solids were collected by suction filtration to afford compoundH3 as a light orange solid (1.60 g, 62% over two steps): ¹H NMR (500MHz, DMSO-d₆) δ 11.11 (bs, 1H), 3.70-3.60 (m, 2H), 2.88-2.76 (m, 4H),2.66 (q, J=7.0 Hz, 2H), 1.48 (s, 9H), 1.11 (t, J=7.0 Hz, 3H). MS (M−H)325.

Step 4: tert-Butyl6-ethyl-3-(morpholine-4-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-ylcarbamate(H4)

To a solution of compound H3 (250 mg, 0.766 mmol), diisopropylethylamine(0.300 mL, 1.69 mmol), and morpholine (100 mg, 1.15 mmol) inN,N-dimethylformamide (3 mL) was added(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(BOP) (678 mg, 1.53 mmol). After stirring at room temperature for 16 h,the reaction mixture was diluted with ethyl acetate (50 mL) and water(75 mL). The layers were separated and the aqueous layer was backextracted with methylene chloride (75 mL) and ethyl acetate (100 mL).The combined organics were dried over anhydrous sodium sulfate,filtered, and concentrated under reduced pressure. The resulting residuewas purified by flash column chromatography on silica gel eluting withmethylene chloride to ethyl acetate to afford compound H4 as a yellowsolid (285 mg, 94%): ¹H NMR (500 MHz, CDCl₃) δ 8.09 (bs, 1H), 3.78-3.45(m, 10H), 2.86-2.78 (m, 2H), 2.74-2.69 (m, 2H), 2.67-2.62 (m, 2H), 1.50(s, 9H), 1.19 (t, J=7.0 Hz, 3H). MS (M+H) 396.

Step 5:(2-Amino-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)(morpholino)methanone(H5)

To a solution of compound H4 (285 mg, 0.721 mmol) in anhydrous methylenechloride (5 mL) was added trifluoroacetic acid (3 mL) at 0° C. Thereaction mixture was gradually warmed to room temperature over 2 h andstirred at room temperature for another 14 h. After this time, thereaction mixture was concentrated under reduced pressure. The resultingresidue was dissolved in methylene chloride (50 mL), washed withsaturated aqueous sodium bicarbonate (50 mL), dried over anhydroussodium sulfate, filtered, and concentrated under reduced pressure toafford compound H5 as a glassy brown solid (145 mg, 68%): ¹H NMR (500MHz, CDCl₃) δ 4.38 (bs, 2H), 3.71-3.63 (m, 4H), 3.65-3.53 (m, 4H), 3.45(s, 2H), 2.73-2.69 (m, 2H), 2.62-2.56 (m, 4H), 1.16 (t, J=7.0 Hz, 3H).MS (M+H) 296.

Step 6:1-(4-Chlorophenyl)-3-[6-ethyl-3-(morpholine-4-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl]urea(H6)

A solution of compound H5 (125 mg, 0.423 mmol) and 4-chlorophenylisocyanate (84.0 mg, 0.547 mmol) in anhydrous tetrahydrofuran (3.5 mL)was stirred at room temperature for 16 h. After this time, the reactionmixture was concentrated under reduced pressure. The resulting residuewas purified by flash column chromatography on silica gel eluting withmethylene chloride to methanol/methylene chloride (1:19) to affordcompound H6 as a glassy brown solid (150 mg, 79%): ¹H NMR (500 MHz,CDCl₃) δ 8.70 (bs, 1H), 7.83 (bs, 1H), 7.21-7.16 (m, 4H), 3.80-3.52 (m,10H), 2.75-2.53 (m, 6H), 1.18 (t, J=7.0 Hz, 3H). MS (M+H) 449.

Step 7:1-(4-Chlorophenyl)-3-[6-ethyl-3-(morpholine-4-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl]ureahydrochloride (H7)

To a solution of compound H6 (150 mg, 0.334 mmol) in anhydrous methylenechloride (3.5 mL) was added hydrochloride (2 M in diethyl ether, 0.220mL, 0.440 mmol). After stirring at room temperature for 20 min, thereaction mixture was diluted with ethyl acetate (20 mL), sonicated, andthe solids collected by suction filtration to afford compound H7 as ayellow solid (136 mg, 84%): ¹H NMR (500 MHz, DMSO-d₆) δ 10.21 (bs, 1H),10.03 (bs, 1H), 9.61 (bs, 1H), 7.49 (d, J=9.0 Hz, 2H), 7.35 (d, J=9.0Hz, 2H), 4.58-4.51 (m, 1H), 4.26-4.17 (m, 1H), 3.81-3.70 (m, 3H),3.62-3.47 (m, 6H), 3.32-3.20 (m, 3H), 2.91-2.83 (m, 1H), 2.78-2.69 (m,1H), 1.30 (t, J=7.0 Hz, 3H). MS (M+H) 449.

Example 96: Preparation of2-[3-(4-Chlorophenyl)ureido]-6-ethyl-N-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 95. MS (M+H) 461. ¹H NMR (300 MHz, CD₃OD) δ 7.53-7.29 (m,4H), 4.70-3.80 (m, 5H), 3.50-3.39 (m, 3H), 3.28-3.15 (m, 2H), 1.46 (t,J=7.1 Hz, 3H).

Example 97: Preparation of2-[3-(4-Chlorophenyl)ureido]-N-(cyclopropylmethyl)-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 95. MS (M+H) 433. ¹H NMR (300 MHz, CD₃OD) δ 7.50-7.29 (m,4H), 4.60-3.80 (m, 3H), 3.55-3.34 (m, 3H), 3.26-3.15 (m, 4H), 1.46 (t,J=7.1 Hz, 3H), 1.20-1.10 (m, 1H), 0.65-0.25 (m, 4H).

Example 98: Preparation of2-[3-(4-Chlorophenyl)ureido]-6-ethyl-N-(pyridin-3-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidedihydrochloride

The title compound was prepared using a similar procedure as describedin Example 95. MS (M+H) 470. ¹H NMR (300 MHz, CD₃OD) δ 8.96 (s, 1H),8.80-8.69 (m, 2H), 8.10-8.06 (m, 1H), 7.53-7.29 (m, 4H), 4.80 (s, 2H),4.70-3.80 (m, 3H), 3.45-3.32 (m, 5H), 1.47 (t, J=7.2 Hz, 3H).

Example 99: Preparation of2-[3-(4-Chlorophenyl)ureido]-N-[2-(dimethylamino)ethyl]-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidedihydrochloride

The title compound was prepared using a similar procedure as describedin Example 95. MS (M+H) 450. ¹H NMR (500 MHz, DMSO-d₆) δ 10.76 (bs, 1H),10.69 (s, 1H), 10.45 (s, 1H), 10.32 (bs, 1H), 7.95 (t, J=5.0 Hz, 1H),7.53-7.34 (m, 4H), 4.53-3.63 (m, 5H), 3.29-3.10 (m, 7H), 2.83 (s, 6H),1.32 (t, J=7.1 Hz, 3H).

Example 100: Preparation of2-[3-(4-Chlorophenyl)ureido]-6-ethyl-N-(2-morpholinoethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidedihydrochloride

The title compound was prepared using a similar procedure as describedin Example 95. MS (M+H) 492. ¹H NMR (300 MHz, DMSO-d₆) δ 11.23 (bs, 1H),10.96 (bs, 1H), 10.67 (s, 1H), 10.48 (s, 1H), 8.06 (t, J=5.1 Hz, 1H),7.54-7.33 (m, 4H), 4.53-3.83 (m, 6H), 3.75-3.50 (m, 10H), 3.40-3.10 (m,4H), 1.33 (t, J=7.2 Hz, 3H).

Example 101: Preparation of2-[3-(4-Chlorophenyl)ureido]-6-ethyl-N-(2-hydroxyethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 95. MS (M+H) 423. ¹H NMR (300 MHz, CD₃OD) δ 7.49-7.28 (m,4H), 4.65-4.25 (m, 2H), 3.90-3.38 (m, 8H), 3.25-3.15 (m, 2H), 1.44 (t,J=7.4 Hz, 3H).

Example 102: Preparation of2-[3-(4-Chlorophenyl)ureido]-6-ethyl-N-(oxetan-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide

The title compound was prepared using a similar procedure as describedin Example 95. MS (M+H) 435. ¹H NMR (300 MHz, CD₃OD) δ 7.53-7.30 (m,4H), 4.46-3.60 (m, 7H), 2.93-2.62 (m, 6H), 1.21 (t, J=7.2 Hz, 3H).

Example 103: Preparation of1-(4-chlorophenyl)-3-[6-ethyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl]ureahydrochloride (15)

Step 1: tert-Butyl6-ethyl-3-[1-(hydroxyimino)ethylcarbamoyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-ylcarbamate(I1)

To a solution of compound H3 (300 mg, 0.919 mmol), diisopropylethylamine(0.320 mL, 1.80 mmol), and N-hydroxyacetimidamide (102 mg, 1.38 mmol) inN,N-dimethylformamide (3.5 mL) was added(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(BOP) (813 mg, 1.84 mmol). After stirring at room temperature for 16 h,the reaction mixture was diluted with ethyl acetate (50 mL) and water(75 mL). The layers were separated and the aqueous layer was backextracted with methylene chloride (75 mL) and ethyl acetate (100 mL).The combined organics were dried over anhydrous sodium sulfate,filtered, and concentrated under reduced pressure. The resulting residuewas purified by flash column chromatography on silica gel eluting withmethylene chloride to ethyl acetate and then to methanol/methylenechloride (1:19) to afford compound I1 as a yellow solid (340 mg, 97%):¹H NMR (500 MHz, CDCl₃) δ 10.33 (bs, 1H), 4.77 (bs, 2H), 3.55 (s, 2H),2.95-2.92 (m, 2H), 2.81-2.76 (m, 2H), 2.62 (q, J=7.0 Hz, 2H), 2.04 (s,3H), 1.51 (s, 9H), 1.19 (t, J=7.0 Hz, 3H). MS (M+H) 383.

Step 2: tert-Butyl6-ethyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-ylcarbamate(12)

A solution of compound I1 (340 mg, 0.889 mmol) in anhydrous 1,4-dioxane(5 mL) was heated to reflux for 14 h. After this time, the reactionmixture was cooled to room temperature and concentrated under reducedpressure. The resulting residue was purified by flash columnchromatography on silica gel eluting with methylene chloride tomethanol/methylene chloride (1:19) to afford compound I2 as a yellowsolid (118 mg, 36%): ¹H NMR (500 MHz, CDCl₃) δ 10.40 (bs, 1H), 3.59 (s,2H), 3.04-3.01 (m, 2H), 2.84-2.81 (m, 2H), 2.64 (q, J=7.0 Hz, 2H), 2.46(s, 3H), 1.57 (s, 9H), 1.19 (t, J=7.0 Hz, 3H). MS (M+H) 365.

Step 3:6-Ethyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-amine(13)

To a solution of compound I2 (87.0 mg, 0.240 mmol) in anhydrousmethylene chloride (3 mL) was added trifluoroacetic acid (3 mL) at 0° C.The reaction mixture was warmed to room temperature and stirred for 24h. After this time, the reaction mixture was concentrated under reducedpressure. The resulting residue was dissolved in methylene chloride (50mL), washed with saturated aqueous sodium bicarbonate (50 mL), driedover anhydrous sodium sulfate, filtered, and concentrated under reducedpressure. The resulting residue was purified by flash columnchromatography on silica gel eluting with methylene chloride tomethanol/methylene chloride (1:19) to afford compound I3 as a yellowsolid (38 mg, 60%): ¹H NMR (500 MHz, CDCl₃) δ 6.17 (bs, 2H), 3.48 (s,2H), 2.99-2.96 (m, 2H), 2.82-2.79 (m, 2H), 2.62 (q, J=7.0 Hz, 2H), 2.39(s, 3H), 1.18 (t, J=7.0 Hz, 3H). MS (M+H) 265.

Step 4:1-(4-Chlorophenyl)-3-[6-ethyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl]urea(14)

To a solution of compound I3 (38.0 mg, 0.140 mmol) in anhydroustetrahydrofuran (2 mL) was added sodium hydride (60% dispersed in oil,10.0 mg, 0.250 mmol) in one portion under nitrogen. After stirring atroom temperature for 5 min, 4-chlorophenyl isocyanate (22.0 mg, 0.140mmol) was added. The reaction mixture was stirred at room temperaturefor 10 min. After this time, the reaction was quenched with slowaddition of methanol (5 mL) and the resulting mixture was concentratedunder reduced pressure. The resulting residue was purified by flashcolumn chromatography on silica gel eluting with methylene chloride tomethanol/methylene chloride (1:19) to afford compound I4 as an off-whitesolid (25 mg, 43%): ¹H NMR (500 MHz, DMSO-d₆) δ 10.44 (bs, 1H), 10.35(bs, 1H), 7.47 (d, J=9.0 Hz, 2H), 7.32 (d, J=9.0 Hz, 2H), 3.52-3.49 (m,2H), 2.88-2.84 (m, 2H), 2.75-2.68 (m, 2H), 2.59-2.52 (m, 2H), 2.47 (s,3H), 1.09 (t, J=7.0 Hz, 3H). MS (M+H) 418.

Step 5:1-(4-Chlorophenyl)-3-[6-ethyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl]ureahydrochloride (I5)

To a solution of compound I4 (25 mg, 0.060 mmol) in anhydrous methylenechloride (5 mL) was added hydrochloride (2 M in diethyl ether, 0.10 mL,0.20 mmol). After stirring at room temperature for 15 min, the reactionmixture was concentrated under reduced pressure and the resultingresidue was triturated with methylene chloride to afford compound I5 asa white solid (22 mg, 81%): ¹H NMR (500 MHz, DMSO-d₆) δ 10.62 (bs, 1H),10.53 (bs, 1H), 10.40 (bs, 1H), 7.57 (d, J=9.0 Hz, 2H), 7.41 (d, J=9.0Hz, 2H), 4.62-4.51 (m, 1H), 4.30-4.19 (m, 1H), 3.81-3.70 (m, 1H),3.31-3.13 (m, 5H), 2.50 (s, 3H), 1.32 (t, J=7.0 Hz, 3H). MS (M+H) 418.

Example 104: Preparation of1-(4-chlorophenyl)-3-[6-ethyl-3-(1,3,4-oxadiazol-2-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl]ureahydrochloride (J5)

Step 1: tert-Butyl6-ethyl-3-(hydrazinecarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-ylcarbamate(J1)

To a solution of compound H3 (500 mg, 1.53 mmol), diisopropylethylamine(1.34 mL, 7.53 mmol), and hydrazine hydrochloride (210 mg, 3.07 mmol) inN,N-dimethylformamide (4 mL) was added(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(BOP) (1.37 g, 3.10 mmol). After stirring at room temperature for 16 h,the reaction mixture was diluted with ethyl acetate (50 mL) and water(75 mL). The layers were separated and the aqueous layer was backextracted with methylene chloride (75 mL) and ethyl acetate (100 mL).The combined organics were dried over anhydrous sodium sulfate,filtered, and concentrated under reduced pressure. The resulting residuewas purified by flash column chromatography on silica gel eluting withmethylene chloride to methanol/methylene chloride (1:9) to affordcompound J1 as a yellow solid (418 mg, 80%): ¹H NMR (300 MHz, CDCl₃) δ10.75 (bs, 1H), 6.93 (bs, 1H), 4.02 (bs, 2H), 3.56 (s, 2H), 2.82-2.78(m, 4H), 2.62 (q, J=7.2 Hz, 2H), 1.52 (s, 9H), 1.18 (t, J=7.2 Hz, 3H).MS (M+H) 341.

Step 2: tert-Butyl6-ethyl-3-(1,3,4-oxadiazol-2-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-ylcarbamate(J2)

A mixture of compound J1 (640 mg, 1.88 mmol) and trimethyl orthoformate(15.0 mL, 137 mmol) were heated to 120° C. for 30 h. After this time,the reaction mixture was cooled to room temperature and concentratedunder reduced pressure. The resulting residue was purified by flashcolumn chromatography on silica gel eluting with methylene chloride tomethanol/methylene chloride (1:19) to afford compound J2 as a yellowsolid (414 mg, 63%): ¹H NMR (300 MHz, CDCl₃) δ 10.23 (bs, 1H), 8.36 (s,1H), 3.49 (s, 2H), 2.99-2.92 (m, 2H), 2.87-2.78 (m, 2H), 2.64 (q, J=7.2Hz, 2H), 1.55 (s, 9H), 1.20 (t, J=7.2 Hz, 3H). MS (M+H) 351.

Step 3:6-Ethyl-3-(1,3,4-oxadiazol-2-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-amine(J3)

To a solution of compound J2 (410 mg, 1.17 mmol) in anhydrous methylenechloride (3 mL) was added trifluoroacetic acid (3 mL) at 0° C. Afterstirring at 0° C. for 3 h, the reaction mixture was concentrated underreduced pressure. The resulting residue was dissolved in methylenechloride (75 mL), washed with saturated aqueous sodium bicarbonate (75mL), dried over anhydrous sodium sulfate, filtered, and concentratedunder reduced pressure. The resulting residue was purified by flashcolumn chromatography on silica gel eluting with methylene chloride tomethanol/methylene chloride (1:9) to afford compound J3 as a yellowsolid (138 mg, 47%): ¹H NMR (500 MHz, CDCl₃) δ 8.28 (s, 1H), 6.06 (bs,2H), 3.49 (s, 2H), 2.93-2.88 (m, 2H), 2.81-2.77 (m, 2H), 2.61 (q, J=7.0Hz, 2H), 1.18 (t, J=7.0 Hz, 3H). MS (M+H) 251.

Step 4:1-(4-Chlorophenyl)-3-[6-ethyl-3-(1,3,4-oxadiazol-2-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl]urea(J4)

To a solution of compound J3 (133 mg, 0.531 mmol) in anhydroustetrahydrofuran (3 mL) was added sodium hydride (60% dispersed in oil,22.0 mg, 0.550 mmol) in one portion at 0° C. under nitrogen. Afterstirring at 0° C. for 5 min, 4-chlorophenyl isocyanate (90.0 mg, 0.590mmol) was added. The reaction mixture was warmed to room temperature andstirred at room temperature for 45 min. After this time, the reactionwas quenched with slow addition of methanol (5 mL) and the resultingmixture was concentrated under reduced pressure. The resulting residuewas purified by flash column chromatography on silica gel eluting withmethylene chloride to methanol/methylene chloride (1:9) to affordcompound J4 as a yellow solid (175 mg, 82%): ¹H NMR (500 MHz, CDCl₃) δ10.62 (bs, 1H), 8.38 (s, 1H), 7.46 (d, J=8.5 Hz, 2H), 7.31 (d, J=8.5 Hz,2H), 7.17 (bs, 1H), 3.60 (s, 2H), 2.97-2.95 (m, 2H), 2.83-2.81 (m, 2H),2.65 (q, J=7.5 Hz, 2H), 1.19 (t, J=7.5 Hz, 3H). MS (M+H) 404.

Step 5:1-(4-Chlorophenyl)-3-[6-ethyl-3-(1,3,4-oxadiazol-2-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl]ureahydrochloride (J5)

To a solution of compound J4 (175 mg, 0.433 mmol) in anhydrous methylenechloride (3 mL) and anhydrous tetrahydrofuran (3 mL) was addedhydrochloride (2 M in diethyl ether, 0.300 mL, 0.600 mmol). Afterstirring at room temperature for 15 min, the reaction mixture wasconcentrated under reduced pressure and the resulting residue wastriturated with methylene chloride to afford compound J5 as a yellowsolid (133 mg, 70%): ¹H NMR (500 MHz, DMSO-d₆) δ 10.63 (s, 1H), 10.46(bs, 1H), 10.42 (s, 1H), 9.37 (s, 1H), 7.55 (d, J=9.0 Hz, 2H), 7.39 (d,J=8.5 Hz, 2H), 4.63-4.56 (m, 1H), 4.29-4.21 (m, 1H), 3.81-3.72 (m, 1H),3.42-3.36 (m, 1H), 3.26-3.12 (m, 4H), 1.32 (t, J=7.0 Hz, 3H). MS (M+H)404.

Example 105: Preparation of2-[1-(4-chlorophenyl)cyclopropanecarboxamido]-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide(K2)

To a solution of 1-(4-chlorophenyl)cyclopropanecarboxylic acid (K1, 131mg, 0.666 mmol) in anhydrous methylene chloride (3 mL) was added oxalylchloride (0.100 mL, 1.17 mmol) followed by 2 drops ofN,N-dimethylformamide at room temperature under nitrogen. After stirringat room temperature for 1 h, the reaction mixture was concentrated underreduced pressure. The resulting residue was dissolved in anhydroustetrahydrofuran (3 mL). To the resulting solution was addeddiisopropylethylamine (0.200 mL, 1.12 mmol) followed by a suspension ofcompound F4 (150 mg, 0.666 mmol) in anhydrous tetrahydrofuran (3 mL).After stirring at room temperature for 3 h, the reaction mixture wasconcentrated under reduced pressure and the resulting residue waspurified by flash column chromatography on silica gel eluting withmethylene chloride to methanol/methylene chloride (1:19). Furtherpurification by trituration with acetonitrile gave compound K2 as alight yellow solid (87 mg, 32%): ¹H NMR (500 MHz, CDCl₃) δ 11.79 (bs,1H), 7.47-7.42 (s, 4H), 5.56 (bs, 2H), 3.57 (s, 2H), 2.82-2.77 (m, 4H),2.62 (q, J=7.0 Hz, 2H), 1.78-1.74 (m, 2H), 1.20-1.12 (m, 5H). MS (M+H)404.

Example 106: Preparation of2-[3-(4-chlorophenyl)-3-methylureido]-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride (L5)

Step 1: tert-Butyl2-amino-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate(L1)

A mixture of 1-ethylpiperidin-4-one (F3, 5.09 g, 40.0 mmol), tert-butyl2-cyanoacetate (5.65 g, 40.0 mmol), sulphur (1.54 g, 48.0 mmol), andmorpholine (6.97 g, 80.0 mmol) in ethanol (200 mL) was stirred at 60° C.for 3 h under nitrogen. After this time, the reaction mixture was cooledto room temperature and concentrated under reduced pressure. Theresulting residue was added saturated aqueous sodium bicarbonate (100mL). The resulting aqueous mixture was extracted with methylene chloride(3×200 mL). The combined organic extracts were dried over anhydroussodium sulfate, filtered, and concentrated under reduced pressure. Theresulting residue was purified by flash column chromatography on silicagel eluting with methanol/methylene chloride (1:9) to afford compound L1as a yellow solid (8.65 g, 76%): ¹H NMR (300 MHz, DMSO-d₆) δ 7.18 (s,2H), 3.26 (s, 2H), 2.62-2.50 (m, 4H), 2.44 (q, J=7.0 Hz, 2H), 1.47 (s,9H), 1.03 (t, J=7.0 Hz, 3H). MS (M+H) 283.

Step 2: tert-Butyl2-[3-(4-chlorophenyl)-3-methylureido]-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate(L2)

To methylene chloride (5 mL) at −78° C. under nitrogen was added asolution of phosgene (0.15 weight/weight in toluene, 4.61 g, 7.00 mmol).The reaction mixture was stirred for 5 min and was added a solution ofcompound L1 (1.41 g, 5.00 mmol) and triethylamine (2.13 g, 21.0 mmol) inmethylene chloride (20 mL) dropwise over 20 min. After addition, thereaction mixture was slowly warmed to room temperature over 2 h. Then tothe reaction mixture was added 4-chloro-N-methylaniline (1.28 g, 9.04mmol). After addition, the reaction mixture was stirred overnight atroom temperature, followed by refluxing for another 2 h. After cooled toroom temperature, the reaction mixture was quenched with saturatedaqueous sodium bicarbonate (60 mL) and extracted with methylene chloride(3×100 mL). The combined organic extracts were dried over anhydroussodium sulfate, filtered, and concentrated under reduced pressure. Theresulting residue was purified by flash column chromatography on silicagel eluting with ethyl acetate to afford partial purified products whichwas further purified by flash column chromatography on silica geleluting with methanol/methylene chloride (1:19) to afford compound L2 asa yellow gum (309 mg, 14%): ¹H NMR (300 MHz, DMSO-d₆) δ 10.51 (s, 1H),7.57 (d, J=8.8 Hz, 2H), 7.48 (d, J=8.8 Hz, 2H), 3.40 (s, 2H), 3.25 (s,3H), 2.66-2.59 (m, 4H), 2.46 (q, J=7.0 Hz, 2H), 1.39 (s, 9H), 1.04 (t,J=7.0 Hz, 3H). MS (M+H) 450.

Step 3:2-[3-(4-Chlorophenyl)-3-methylureido]-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylicacid hydrochloride (L3)

To a stirred mixture of compound L2 (303 mg, 0.673 mmol) in methylenechloride (6 mL) and toluene (2 mL) at room temperature was addedtrifluoroacetic acid (9.21 g, 80.8 mmol) dropwise over 2 min. Afteraddition, the reaction mixture was stirred for another 2.5 h andconcentrated under reduced pressure. The resulting residue was mixedwith hydrochloride (2 M in diethyl ether, 6.00 mL, 12.0 mmol) and thenconcentrated, this procedure was repeated two times, to afford compoundL3 as a brown gum (290 mg, >99%): MS (M+H) 394. This product was used innext step without further purification.

Step 4:2-[3-(4-Chlorophenyl)-3-methylureido]-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide(L4)

To a stirred mixture of compound L3 (290 mg, 0.736 mmol) inN,N-dimethylformamide (5 mL) was added ammonia solution (0.5 M in1,4-dioxane, 20.0 mL, 10.0 mmol), ammonium chloride (535 mg, 10.0 mmol),triehtylamine (1.01 g, 10.0 mmol), and(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(BOP) (1.31 g, 2.95 mmol). After addition, the reaction mixture wasstirred overnight at room temperature and concentrated under reducedpressure. The resulting residue was mixed with saturated aqueous sodiumbicarbonate (40 mL) and the resulting aqueous mixture was extracted withmethylene chloride (3×100 mL). The combined organic extracts were driedover anhydrous sodium sulfate, filtered, and concentrated under reducedpressure. The resulting residue was purified by flash columnchromatography on silica gel eluting with methanol/methylene chloride(1:9) to afford compound L4 as a pale yellow solid (125 mg, 47% over twosteps): ¹H NMR (300 MHz, DMSO-d₆) δ 11.42 (s, 1H), 7.54 (d, J=8.7 Hz,2H), 7.45 (d, J=8.7 Hz, 2H), 7.43 (bs, 1H), 6.60 (bs, 1H), 3.43 (s, 2H),3.23 (s, 3H), 2.70 (d, J=4.8 Hz, 2H), 2.61 (d, J=4.8 Hz, 2H), 2.48 (q,J=7.0 Hz, 2H), 1.06 (t, J=7.0 Hz, 3H). MS (M+H) 393.

Step 5:2-[3-(4-Chlorophenyl)-3-methylureido]-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride (L5)

To a mixture of compound L4 (47.0 mg, 0.120 mmol) in methylene chloride(10 mL) at room temperature was added hydrochloride (2 M in diethylether, 1.00 mL, 2.00 mmol). The resulting mixture was sonicated for 10min, and then concentrated under reduced pressure. The resulting residuewas dissolved in a mixture of methanol (2 mL) and water (2 mL) and thenlyophilized to afford compound L5 as a yellow solid (50 mg, 97%): ¹H NMR(300 MHz, DMSO-d₆) δ 11.47 (s, 1H), 10.48 (bs, 1H), 7.56 (d, J=8.7 Hz,2H), 7.46 (d, J=8.7 Hz, 2H), 7.19 (bs, 2H), 4.53-4.47 (m, 1H), 4.21-4.12(m, 1H), 3.65-3.60 (m, 1H), 3.32-2.92 (m, 8H), 1.29 (t, J=7.2 Hz, 3H).MS (M+H) 393.

Example 107: Preparation of6-ethyl-2-ureido-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride (M2)

Step 1:6-Ethyl-2-ureido-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide(M1)

To a stirred mixture of compound F4 (451 mg, 2.00 mmol) in acetic acid(6 mL) at room temperature was added a solution of sodium cyanate (169mg, 2.60 mmol) in water (2.5 mL) dropwise over 2 min. After addition,the reaction mixture was stirred for another 2 h and then concentratedunder reduced pressure. The resulting residue was mixed with saturatedaqueous sodium bicarbonate (50 mL) and extracted with methylene chloride(3×150 mL). The combined organic extracts were dried over anhydroussodium sulfate, filtered, and concentrated under reduced pressure. Theresulting residue was purified by flash column chromatography on silicagel eluting with methanol/methylene chloride (15:85) to afford compoundM1 as a yellow solid (125 mg, 23%): ¹H NMR (300 MHz, DMSO-d₆) δ 10.45(s, 1H), 7.31 (bs, 1H), 6.77 (bs, 3H), 3.41 (s, 2H), 2.73 (d, J=4.8 Hz,2H), 2.63 (d, J=4.8 Hz, 2H), 2.50-2.45 (m, 2H), 1.06 (t, J=7.0 Hz, 3H).MS (M+H) 269.

Step 2:6-Ethyl-2-ureido-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride (M2)

To a mixture of compound M1 (108 mg, 0.400 mmol) in water (6 mL) andmethanol (2 mL) at room temperature was added 1 M hydrochloric acid(0.600 mL, 0.600 mmol). After addition, the mixture was sonicated toform clear solution and then lyophilized to afford compound M2 as a greysolid (107 mg, 88%): ¹H NMR (300 MHz, DMSO-d₆) δ 10.57 (bs, 1H), 10.46(s, 1H), 7.65-6.60 (m, 4H), 4.48-4.43 (m, 1H), 4.19-4.10 (m, 1H),3.37-3.14 (m, 4H), 3.05 (bs, 2H), 1.30 (t, J=7.2 Hz, 3H). MS (M+H) 269.

Example 108: Preparation of6-ethyl-2-formamido-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride (N2)

Step 1:6-Ethyl-2-formamido-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide(N1)

A mixture of compound F4 (225 mg, 1.00 mmol) in formic acid (5 mL) andwater (1 mL) was stirred overnight at room temperature. After that time,the reaction mixture was concentrated under reduced pressure. Theresidue was mixed with saturated aqueous sodium bicarbonate (50 mL) andextracted with methylene chloride (3×150 mL). The combined organicextracts were dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure. The resulting residue was purifiedby flash column chromatography on silica gel eluting withmethanol/methylene chloride (15:85) to afford compound N1 as anoff-white solid (208 mg, 82%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.44 (s,1H), 8.40 (s, 1H), 7.52 (bs, 1H), 7.03 (bs, 1H), 3.48 (s, 2H), 2.76 (d,J=4.8 Hz, 2H), 2.65 (d, J=4.8 Hz, 2H), 2.54-2.47 (m, 2H), 1.07 (t, J=7.0Hz, 3H). MS (M+H) 254.

Step 2:6-Ethyl-2-formamido-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride (N2)

To a mixture of compound N1 (152 mg, 0.600 mmol) in water (6 mL) andmethanol (2 mL) at room temperature was added 1 M hydrochloric acid(1.00 mL, 1.00 mmol). After addition, the mixture was sonicated to formclear solution and then lyophilized to afford compound N2 as a whitesolid (165 mg, 95%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.49 (s, 1H), 10.94(bs, 1H), 8.44 (s, 1H), 7.61 (bs, 1H), 7.37 (bs, 1H), 4.55-4.49 (m, 1H),4.25-4.17 (m, 1H), 3.29-3.07 (m, 6H), 1.31 (t, J=7.2 Hz, 3H). MS (M+H)254.

Example 109: Preparation of2-({2-[(4-chlorophenyl)amino]-3,4-dioxocyclobut-1-en-1-yl}amino)-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride (O6)

Step 1: 3-[(4-Chlorophenyl)amino]-4-methoxycyclobut-3-ene-1,2-dione (O2)

To a stirred mixture of 3,4-dimethoxycyclobut-3-ene-1,2-dione (O1, 1.00g, 7.04 mmol) in methanol (7 mL) at 0° C. under nitrogen was added asolution of 4-chloroaniline (0.898 g, 7.04 mmol) in methanol (8 mL)dropwise over 0.5 h. After addition, the reaction mixture was slowlywarmed to room temperature and stirred at room temperature for another 2days. The reaction mixture was filtered. The filter cake was washed withcold methanol (5 mL) and dried under reduced pressure to afford compoundO2 as a yellow solid (1.48 g, 89%): ¹H NMR (300 MHz, DMSO-d₆) δ 10.84(s, 1H), 7.44-7.35 (m, 4H), 4.38 (s, 3H). MS (M+H) 238.

Step 2: tert-Butyl2-({2-[(4-chlorophenyl)amino]-3,4-dioxocyclobut-1-en-1-yl}amino)-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate(O3)

To a stirred mixture of sodium hydride (60% in mineral oil, 240 mg, 6.00mmol) in anhydrous tetrahydrofuran (5 mL) at 0° C. under nitrogen wasadded the solution of compound L1 (1.13 g, 4.00 mmol) in anhydroustetrahydrofuran (15 mL) dropwise over 10 min. After addition, thereaction mixture was stirred for another 15 min. Then to the reactionmixture was added a solution of compound O2 (0.951 g, 4.00 mmol) inanhydrous tetrahydrofuran (20 mL) over 5 min. After addition, thereaction mixture was stirred at 0° C. for 0.5 h and then heated to 50°C. for another 2 h. After cooled to room temperature, the reactionmixture was quenched with saturated aqueous sodium bicarbonate (100 mL).The aqueous mixture was extracted with methylene chloride (2×200 mL).The combined organic extracts were dried over anhydrous sodium sulfate,filtered, and concentrated under reduced pressure. The resulting residuewas purified by flash column chromatography on silica gel eluting withmethanol/ethyl acetate (1:19) to afford compound O3 as a yellow solid(445 mg, 23%): ¹H NMR (500 MHz, DMSO-d₆) δ 10.42 (bs, 2H), 7.43-7.38 (m,4H), 3.54 (s, 2H), 2.89-2.60 (m, 4H), 2.57-2.54 (m, 2H), 1.48 (s, 9H),1.09 (t, J=7.0 Hz, 3H). MS (M−H) 486.

Step 3:2-({2-[(4-Chlorophenyl)amino]-3,4-dioxocyclobut-1-en-1-yl}amino)-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylicacid (O4)

To a stirred mixture of compound O3 (293 mg, 0.600 mmol) in methylenechloride (12 mL) and toluene (3 mL) at room temperature under nitrogenwas added trifluoroacetic acid (6.91 g, 60.6 mmol) dropwise over 2 min.After addition, the reaction mixture was stirred for another 2 h. Thereaction mixture was diluted with toluene (20 mL) and concentrated underreduced pressure. The resulting residue was purified by flash columnchromatography on silica gel eluting with ammoniumhydroxide/methanol/methylene chloride (1:14:85) to afford compound O4 asyellow solid (120 mg, 46%): MS (M−H) 430.

Step 4:2-({2-[(4-Chlorophenyl)amino]-3,4-dioxocyclobut-1-en-1-yl}amino)-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide(O5)

To a stirred mixture of compound O4 (110 mg, 0.255 mmol) in anhydrousN,N-dimethylformamide (4 mL) at room temperature under nitrogen wasadded sequentially ammonium chloride (535 mg, 10.0 mmol), triethylamine(1.02 g, 10.0 mmol), ammonia solution (0.5 M in 1,4-dioxane, 6.00 mL,3.00 mmol), and (benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumhexafuorophosphate (BOP) (339 mg, 0.766 mmol). After addition, thereaction mixture was stirred for 4 h and then diluted with water (6 mL).The resulting aqueous mixture was lyophilized. The resulting residue wasdiluted with saturated aqueous sodium bicarbonate (10 mL) and thenextracted with methylene chloride (3×30 mL). The combined organicextracts were dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure. The resulting residue was purifiedtwo times by flash column chromatography on silica gel eluting withmethanol/methylene chloride (15:85) to afford compound O5 as a yellowsolid (34 mg, 31%): MS (M+H) 431.

Step 5:2-({2-[(4-Chlorophenyl)amino]-3,4-dioxocyclobut-1-en-1-yl}amino)-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride (O6)

To mixture of compound O5 (28 mg, 0.065 mmol) in methanol (3 mL) wasadded 1 M hydrochloric acid (0.10 mL, 0.10 mmol). The mixture wassonicated for 3 min, diluted with water (6 mL), and lyophilized toafford compound O6 as a brown solid (25 mg, 83%): ¹H NMR (300 MHz,DMSO-d₆) δ 10.85 (s, 1H), 10.77 (s, 1H), 10.34 (bs, 1H), 7.70-7.41 (m,6H), 4.62-4.56 (m, 1H), 4.29-4.20 (m, 1H), 3.71-3.62 (m, 1H), 3.52-3.12(m, 3H), 3.03 (bs, 2H), 1.30 (t, J=7.0 Hz, 3H). MS (M+H) 431.

Example 110: Preparation of Ethyl2-({2-[(4-chlorophenyl)amino]-3,4-dioxocyclobut-1-en-1-yl}amino)-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylatehydrochloride

The title compound was prepared using a similar procedure as describedin Example 109. MS (M+H) 458. ¹H NMR (300 MHz, DMSO-d₆) δ 11.18 (s, 1H),10.95 (s, 1H), 10.37 (bs, 1H), 7.49 (d, J=5.1 Hz, 2H), 7.44 (d, J=5.1Hz, 2H), 4.61-4.57 (m, 1H), 4.29-4.20 (m, 3H), 3.71-3.68 (m, 1H),3.40-3.21 (m, 3H), 3.18-3.03 (m, 2H), 1.33-1.22 (m, 6H).

Example 111: Preparation of(+/−)-2-[3-(4-chlorophenyl)ureido]-1′-methyl-5,7-dihydro-4H-spiro(benzo[b]thiophene-6,2′-pyrrolidine)-3-carboxamidehydrochloride [(+/−)-P8]

Step 1: 1,4-Dioxa-9-azadispiro[4.2.4.2]tetradecan-10-one (P2)

A stirred mixture of 1-azaspiro[4.5]decane-2,8-dione (P1, 2.00 g, 12.0mmol), ethylene glycol (2.96 g, 47.7 mmol), and 4-methylbenzenesulfonicacid (100 mg, 0.735 mmol) in toluene (100 mL) was refluxed for 20 h withDean-Stark apparatus to remove water. After this time, the reactionmixture was cooled to room temperature and concentrated under reducedpressure. The resulting residue was mixed with saturated aqueous sodiumbicarbonate (100 mL) and the resulting aqueous mixture was extractedwith 5% methanol/ethyl acetate (4×150 mL). The combined organic extractswere dried over anhydrous sodium sulfate, filtered, and concentratedunder reduced pressure to afford compound P2 as an off-white solid (2.41g, 95%): ¹H NMR (300 MHz, DMSO-d₆) δ 5.82 (bs, 1H), 3.95 (s, 4H), 2.41(t, J=8.0 Hz, 2H), 1.99 (t, J=8.0 Hz, 2H), 1.80-1.65 (m, 8H). MS (M+H)212.

Step 2: 1,4-Dioxa-9-azadispiro[4.2.4.2]tetradecane (P3)

To a stirred mixture of compound P2 (2.40 g, 11.4 mmol) in anhydroustetrahydrofuran (50 mL) at 0° C. under nitrogen was added lithiumaluminium hydride solution (1.0 M in tetrahydrofuran, 18.2 mL, 18.2mmol) dropwise over 10 min. After addition, the reaction mixture wasstirred at 0° C. for another 20 min, followed with 4 h refluxing. Thereaction mixture was cooled to 0° C. and to the reaction mixture wasadded another portion of lithium aluminium hydride (1.0 M intetrahydrofuran, 9.00 mL, 9.00 mmol) dropwise over 5 min. Afteraddition, the reaction mixture was refluxed for another 4 h. Aftercooled to 0° C., the reaction was quenched by slow addition of sodiumsulfate decahydrate. To the mixture was added triethylamine (3 mL). Theresulting mixture was stirred for 0.5 h and filtered through a shortsilica gel plug. The solid cake was washed with 5%diethylamine/tetrahydrofuran (3×100 mL) and filtered. The combinedfiltrate was concentrated under reduced pressure. The resulting residuewas purified by flash column chromatography on silica gel eluting withammonium hydroxide/methanol/methylene chloride (1:14:85) to affordcompound P3 as a colourless oil (1.39 g, 62%): MS (M+H) 198.

Step 3: 1,4-Dioxa-N-methyl-9-azadispiro[4.2.4.2]tetradecane (P4)

The formaldehyde aqueous solution (37% w/w in water, 10 mL) wasextracted with methylene chloride (100 mL). The organic extract wasdried over anhydrous sodium sulfate and filtered. The resulting stocksolution was used for the following reaction without characterization.

To a stirred solution of compound P3 (1.39 g, 7.05 mmol) in methylenechloride (50 mL) under nitrogen was added formaldehyde stock solution(30.0 mL) in one portion, followed with acetic acid (420 mg, 6.99 mmol).After addition, the reaction mixture was stirred for another 10 min.Then to the reaction mixture was added sodium triacetoxyborohydride(4.48 g, 21.1 mmol) in one portion. After stirred for 40 min, to thereaction mixture was added another portion of formaldehyde stocksolution (10.0 mL) and sodium triacetoxyborohydride (2.98 g, 14.1 mmol).After addition, the reaction mixture was stirred for another 20 min.After this time, the reaction was quenched by slow addition of saturatedaqueous sodium bicarbonate (80 mL). The resulting aqueous mixture wasextracted with methylene chloride (3×200 mL). The combined organicextracts were dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure to afford compound P4 as colourlessoil (1.42 g, 95%): MS (M+H) 212.

Step 4: 1-Methyl-1-azaspiro[4.5]decan-8-one (P5)

To a stirred mixture of compound P4 (1.42 g, 6.72 mmol) intetrahydrofuran (10 mL) and acetone (2 mL) under nitrogen was added 4 Mhydrochloric acid (10.0 mL, 40.0 mmol). After addition, the reactionmixture was heated to reflux for 4 h. After cooled to room temperature,the reaction was quenched by slow addition of saturated aqueous sodiumbicarbonate (80 mL). The resulting aqueous mixture was extracted with 5%methanol in methylene chloride (4×100 mL). The combined organic extractswere dried over anhydrous sodium sulfate, filtered, and concentratedunder reduced pressure. The resulting residue was purified by flashcolumn chromatography on silica gel eluting with methanol/methylenechloride (15:85) to provide compound P5 as a colourless oil (1.01 g,90%): ¹H NMR (300 MHz, CDCl₃) δ 2.83 (t, J=6.9 Hz, 2H), 2.46-2.39 (m,4H), 2.30 (s, 3H), 2.00-1.82 (m, 6H), 1.78-1.60 (m, 2H). MS (M+H) 168.

Step 5:(+/−)-2-Amino-1′-methyl-5,7-dihydro-4H-spiro(benzo[b]thiophene-6,2′-pyrrolidine)-3-carboxamide[(+/−)-P6]

A stirred mixture of compound P5 (1.00 g, 5.98 mmol), 2-cyanoacetamide(603 mg, 7.17 mmol), sulphur (230 mg, 7.17 mmol), and morpholine (1.04g, 11.9 mmol) in ethanol (50 mL) was heated to reflux for 3 h undernitrogen. After cooled to room temperature, the reaction mixture wasconcentrated under reduced pressure. The resulting residue was purifiedby flash column chromatography on silica gel eluting withmethanol/methylene chloride (15:85) to provide compound (+/−)-P6 as ayellow solid (1.01 g, 90%): MS (M+H) 266.

Step 6:(+/−)-2-[3-(4-Chlorophenyl)ureido]-1′-methyl-5,7-dihydro-4H-spiro(benzo[b]thiophene-6,2′-pyrrolidine)-3-carboxamide[(+/−)-P7]

To a stirred mixture of compound (+/−)-P6 (305 mg, 1.15 mmol) intetrahydrofuran (25 mL) at room temperature under nitrogen was added4-chlorophenyl isocyanate (212 mg, 1.38 mmol) in one portion. Afteraddition, the reaction mixture was stirred overnight under nitrogen.After that time, the reaction mixture was concentrated under reducedpressure. The resulting residue was purified by flash columnchromatography on silica gel eluting with ammoniumhydroxide/methanol/methylene chloride (1:14:85) to provide compound(+/−)-P7 as a white solid (324 mg, 67%): ¹H NMR (300 MHz, DMSO-d₆) δ10.91 (s, 1H), 10.13 (s, 1H), 7.50 (d, J=9.0 Hz, 2H), 7.45 (bs, 1H),7.33 (d, J=9.0 Hz, 2H), 6.91 (bs, 1H), 2.81-2.62 (m, 5H), 2.27-2.21 (m,4H), 1.70-1.45 (m, 6H). MS (M+H) 419.

Step 7:(+/−)-2-[3-(4-Chlorophenyl)ureido]-1′-methyl-5,7-dihydro-4H-spiro(benzo[b]thiophene-6,2′-pyrrolidine)-3-carboxamidehydrochloride [(+/−)-P8]

To a mixture of compound (+/−)-P7 (100 mg, 0.240 mmol) in methanol (15mL) was added 1 M hydrochloric acid (0.500 mL, 0.500 mmol) dropwise.After addition, the reaction mixture was stirred for 10 min, dilutedwith water (20 mL), and lyophilized to afford compound (+/−)-P8 as awhite solid (104 mg, 95%): ¹H NMR (300 MHz, DMSO-d₆) δ 10.88 and 10.82(2 s, 1H), 10.68 and 10.58 (2 s, 1H), 10.21 (s, 1H), 7.75-6.85 (m, 6H),3.60-3.52 (m, 1H), 3.30-2.68 (m, 8H), 2.20-1.73 (m, 6H). MS (M+H) 419.

Example 112: Preparation of6-[3-(4-chlorophenyl)ureido]-2-ethyl-1,2,3,4-tetrahydroisoquinoline-5-carboxamidehydrochloride (Q10)

Step 1: tert-Butyl6-amino-5-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (Q2)

To a solution of tert-butyl6-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate (Q1, 683 mg, 2.75mmol) in methylene chloride (40 mL) was added N-bromosuccinimide (NBS)(490 mg, 2.75 mmol) at 0° C. The reaction mixture was stirred for 30 minand then diluted with methylene chloride (200 mL). The resultingsolution was washed with water (50 mL), saturated aqueous sodiumbicarbonate (50 mL), and brine (50 mL), dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure. Theresulting residue was purified by flash column chromatography on silicagel eluting with 12% to 30% ethyl acetate/hexanes to afford compound Q2as a white solid (743 mg, 83%): ¹H NMR (500 MHz, CDCl₃) δ 6.86 (d, J=8.2Hz, 1H), 6.65 (d, J=8.2 Hz, 1H), 4.47 (s, 2H), 4.07 (s, 2H), 3.63 (t,J=5.8 Hz, 2H), 2.82 (t, J=5.8 Hz, 2H), 1.48 (s, 9H).

Step 2: tert-Butyl6-amino-5-cyano-3,4-dihydroisoquinoline-2(1H)-carboxylate (Q3)

To a degassed mixture of compound Q2 (656 mg, 2.01 mmol), zinc dust (131mg, 2.01 mmol), zinc cyanide (472 mg, 4.02 mmol) in anhydrous N,N-dimethylformamide (8 mL) was addedtris(dibenzylideneacetone)dipalladium(0) (920 mg, 1.01 mmol) followed bytri-tert-butylphosphine (409 mg, 2.02 mmol) at room temperature. Afteraddition, the reaction mixture was stirred for 3 days under nitrogen andthen diluted with ethyl acetate (200 mL), water (50 mL), and saturatedaqueous sodium bicarbonate (10 mL). The resulting mixture was filteredand the filter cake was washed with ethyl acetate (50 mL). The combinedfiltrate layers were separated. The organic layer was washed with water(3×30 mL) and brine (50 mL), dried over anhydrous sodium sulfate,filtered, and concentrated under reduced pressure. The resulting residuewas purified by flash column chromatography on silica gel eluting with20% to 30% ethyl acetate/hexanes to afford compound Q3 as a yellow form(435 mg, 79%): ¹H NMR (500 MHz, CDCl₃) δ 7.05 (d, J=8.4 Hz, 1H), 6.59(d, J=8.4 Hz, 1H), 4.43 (s, 2H), 4.35 (s, 2H), 3.65 (t, J=5.8 Hz, 2H),2.90 (t, J=5.8 Hz, 2H), 1.49 (s, 9H). MS (M+H—C₄H₈) 218.

Step 3: tert-Butyl6-{[(benzyloxy)carbonyl]amino}-5-cyano-3,4-dihydroisoquinoline-2(1H)-carboxylate(Q4)

To a stirred mixture of compound Q3 (569 mg, 2.08 mmol), sodiumbicarbonate (489 mg, 5.82 mmol) in anhydrous tetrahydrofuran (15 mL) wasadded benzyl chloroformate (848 mg, 4.97 mmol) at 0° C. under nitrogen.After addition, the reaction mixture was warmed to room temperature andstirred for 26 h. After this time, the reaction was quenched withsaturated aqueous sodium bicarbonate (80 mL). The resulting mixture wasextracted with methylene chloride (3×50 mL). The combined extracts weredried over anhydrous sodium sulfate, filtered, and concentrated underreduced pressure. The resulting residue was purified by flash columnchromatography on silica gel eluting with 20% ethyl acetate/hexanes toafford compound Q4 as a light yellow form (606 mg, 72%): ¹H NMR (300MHz, CDCl₃) δ 8.06 (d, J=8.6 Hz, 1H), 7.44-7.28 (m, 6H), 7.16 (s, 1H),5.23 (s, 2H), 4.53 (s, 2H), 3.68 (t, J=5.8 Hz, 2H), 2.96 (t, J=5.8 Hz,2H), 1.49 (s, 9H). MS (M+H—C₄H₈) 352.

Step 4: Benzyl (5-cyano-1,2,3,4-tetrahydroisoquinolin-6-yl)carbamatetrifluoroacetate (Q5)

To a stirred solution of compound Q4 (468 mg, 1.15 mmol) in methylenechloride (3 mL) was added trifluoroacetic acid (1.5 mL) at roomtemperature. After stirring for 1 h, the reaction mixture wasconcentrated under reduced pressure. The resulting residue was driedunder high vacuum to afford compound Q5 as a light brown form (656mg, >99%): MS (M+H) 308. This product was used in the next step withoutfurther purification.

Step 5: Benzyl(5-cyano-2-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)carbamate (Q6)

To a stirred mixture of compound Q5 (127 mg, 0.292 mmol) and acetic acid(0.56 mL) in anhydrous tetrahydrofuran (1 mL) was added sodiumborohydride (55.0 mg, 1.45 mmol) at 0° C. under nitrogen. Afteraddition, the reaction mixture was heated to 60° C. for 4 h and cooledto room temperature. The reaction mixture was concentrated and theresidue was mixed with saturated aqueous sodium bicarbonate (50 mL). Theresulting mixture was extracted with methylene chloride (3×30 mL). Thecombined extracts were dried over anhydrous sodium sulfate, filtered,and concentrated under reduced pressure. The resulting residue waspurified by flash column chromatography on silica gel eluting with 4% to10% methanol/methylene chloride to afford compound Q6 as a light yellowsolid (62 mg, 63% over two steps): MS (M+H) 336.

Step 6: 6-Amino-2-ethyl-1,2,3,4-tetrahydroisoquinoline-5-carbonitrile(Q7)

A mixture of compound Q6 (60.0 mg, 0.179 mmol) and 10% palladium oncarbon (50% wet, 10 mg) in methanol (15 mL) was stirred under hydrogen(1 atm) at room temperature for 6 h. After this time, the reactionmixture was filtered through a short pad of Celite and washed withmethanol (50 mL). The combined filtrate was concentrated under reducedpressure to afford compound Q7 as an off-white solid (33 mg, 92%): ¹HNMR (300 MHz, CDCl₃) δ 6.98 (d, J=8.4 Hz, 1H), 6.53 (d, J=8.4 Hz, 1H),4.30 (bs, 2H), 3.48 (s, 2H), 2.97 (t, J=5.8 Hz, 2H), 2.73 (t, J=5.8 Hz,2H), 2.57 (q, J=7.2 Hz, 2H), 1.18 (t, J=7.2 Hz, 3H). MS (M+H) 202.

Step 7: 6-Amino-2-ethyl-1,2,3,4-tetrahydroisoquinoline-5-carboxamide(Q8)

A solution of compound Q7 (163 mg, 0.810 mmol) and potassium hydroxide(909 mg, 16.2 mmol) in water (20 mL) was heated to reflux for 18 h.After this time, the reaction mixture was cooled to room temperature,diluted with water (10 mL), neutralized with 2 N hydrochloric acid to pH8, and concentrated under reduced pressure. The resulting residue wastriturated with methanol (3×30 mL) and filtered. The combined filtratewas concentrated under reduced pressure. The resulting residue waspurified by flash column chromatography on silica gel eluting with 50%to 60% methanol/methylene chloride to afford compound Q8 as an off-whitesolid (219 mg, >99%): MS (M+H) 220. This product was used in the nextstep without further purification.

Step 8:6-[3-(4-Chlorophenyl)ureido]-2-ethyl-1,2,3,4-tetrahydroisoquinoline-5-carboxamide(Q9)

A solution of compound Q8 (263 mg, 0.960 mmol) and 4-chlorophenylisocyanate (147 mg, 0.960 mmol) in anhydrous N,N-dimethylformamide (5mL) was stirred under nitrogen at room temperature for 19 h. After thistime, the reaction mixture was concentrated under reduced pressure. Theresulting residue was triturated with a mixture of methanol (5 mL),methylene chloride (10 mL), concentrated ammonium hydroxide aqueoussolution (1 mL), and hexanes (20 mL) to afford compound Q9 as a whitesolid (143 mg, 40% over two steps): MS (M+H) 373.

Step 9:6-[3-(4-Chlorophenyl)ureido]-2-ethyl-1,2,3,4-tetrahydroisoquinoline-5-carboxamidehydrochloride (Q10)

A mixture of compound Q9 (66.0 mg, 0.177 mmol) and hydrochloride (2 M indiethyl ether, 0.097 mL, 0.194 mmol) in methanol (2 mL) and methylenechloride (4 mL) was stirred at room temperature for 5 min. After thistime, the reaction mixture was concentrated under reduced pressure. Theresulting residue was triturated with a mixture of methanol (0.5 mL),methylene chloride (5 mL), ethyl acetate (3 mL), and hexanes (3 mL) toafford compound Q10 as a white solid (57 mg, 79%): ¹H NMR (500 MHz,DMSO-d₆) δ 10.50 (bs, 1H), 9.64 (s, 1H), 8.07 (s, 2H), 7.81 (d, J=8.6Hz, 1H), 7.80 (s, 1H), 7.48-7.30 (m, 4H), 7.18 (d, J=8.6 Hz, 1H),4.51-4.19 (m, 2H), 3.67-3.65 (m, 1H), 3.29-3.07 (m, 5H), 1.33 (t, J=7.2Hz, 3H). MS (M+H) 373.

Example 113: Preparation of2-[3-(4-chlorophenyl)-1-ethylureido]-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride (R3)

Step 1:6-Ethyl-2-(ethylamino)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide(R1)

To a stirred mixture of compound F4 (200 mg, 0.888 mmol), acetaldehyde(5 M in tetrahydrofuran, 0.360 mL, 1.80 mmol), acetic acid (two drops),anhydrous magnesium sulfate (200 mg) in anhydrous methanol (6 mL) andanhydrous tetrahydrofuran (3 mL) was added sodium cyanoborohydride (167mg, 2.66 mmol) at room temperature under nitrogen. The reaction mixturewas stirred for 23 h and then filtered. The filtrate was concentrated.The resulting residue was purified by flash column chromatography onsilica gel eluting with 10% to 20% methanol/methylene chloride to affordcompound R1 as a colourless syrup (181 mg, 80%): MS (M+H) 254.

Step 2:2-[3-(4-Chlorophenyl)-1-ethylureido]-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide(R2)

A solution of compound R1 (181 mg, 0.714 mmol) and 4-chlorophenylisocyanate (110 mg, 0.714 mmol) in anhydrous N,N-dimethylformamide (5mL) was heated to 60° C. for 18 h, cooled to room temperature, andconcentrated under reduced pressure. The resulting residue was purifiedby flash column chromatography on silica gel eluting with 4% to 20%methanol/methylene chloride to afford compound R2 as a light yellowsolid (72 mg, 25%): MS (M+H) 407.

Step 3:2-[3-(4-Chlorophenyl)-1-ethylureido]-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidetrifluoroacetate (R3)

To a solution of compound R2 (72.0 mg, 0.177 mmol) in acetonitride (2mL) and water (1 mL) was added trifluoroacetic acid (22.0 mg, 0.193mmol). The resulting solution was lyophilized to afford compound R3 as awhite solid (56 mg, 61%): ¹H NMR (500 MHz, DMSO-d₆) δ 9.95 (bs, 1H),8.67 (s, 1H), 7.73 (s, 1H), 7.46 (s, 1H), 7.43-7.30 (m, 4H), 4.65-4.27(m, 2H), 3.73-2.94 (m, 8H), 1.30 (t, J=7.2 Hz, 3H), 1.10 (t, J=7.1 Hz,3H). MS (M+H) 407.

Example 114: Preparation of2-[3-(4-chlorophenyl)ureido)-7-ethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepine-3-carboxamidehydrochloride (S9)

Step 1: tert-Butyl2-amino-3-carbamoyl-5,6-dihydro-4H-thieno[2,3-c]azepine-7(8H)-carboxylate(S2) and tert-butyl2-amino-3-carbamoyl-7,8-dihydro-4H-thieno[2,3-d]azepine-6(5H)-carboxylate(S3)

A mixture of compound S1 (1.00 g, 4.69 mmol), 2-cyanoacetamide (394 mg,4.69 mmol), sulphur (150 mg, 4.69 mmol), and morpholine (410 mg, 4.71mmol) in ethanol (10 mL) was heated to reflux for 4 h under nitrogen.After cooled to room temperature, the reaction mixture was concentratedunder reduced pressure. The resulting residue was purified by flashcolumn chromatography on silica gel eluting with 4% methanol/methylenechloride to provide an inseparable mixture of isomers S2 and compound S3as a yellow solid (564 mg, 39%): MS (M+H) 312.

Step 2: tert-Butyl3-carbamoyl-2-[3-(4-chlorophenyl)ureido]-5,6-dihydro-4H-thieno[2,3-c]azepine-7(8H)-carboxylate(S4) and tert-butyl3-carbamoyl-2-[3-(4-chlorophenyl)ureido]-7,8-dihydro-4H-thieno[2,3-d]azepine-6(5H)-carboxylate(S5)

To a stirred mixture of compound S2 and S3 (300 mg, 0.963 mmol) inN,N-dimethylformamide (2 mL) at room temperature under nitrogen wasadded 4-chlorophenyl isocyanate (148 mg, 0.964 mmol). After addition,the reaction mixture was stirred for 21 h. After this time, the reactionmixture was concentrated under reduced pressure. The resulting residuewas purified by flash column chromatography on silica gel eluting with50% ethyl acetate/methylene chloride to provide an inseparable mixtureof isomers S4 and S5 as a white solid (375 mg, 84%): MS (M+Na) 487.

Step 3:2-[3-(4-Chlorophenyl)ureido]-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepine-3-carboxamidetrifluoroacetae (S6) and2-[3-(4-chlorophenyl)ureido]-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine-3-carboxamidetrifluoroacetae (S7)

To a mixture of compound S4 and S5 (374 mg, 0.804 mmol) in methylenechloride (4 mL) was added trifluoroacetic acid (2 mL). After addition,the reaction mixture was stirred for 1 h and then concentrated underreduced pressure. The resulting residue was purified by reverse phasesemi-preparative HPLC, eluting with 0.05% TFA in acetonitrile/water(gradient from 10% to 100%, Phenomenex Luna column) to afford compoundS6 as a white solid (188 mg, 49%) and compound S7 as a white solid (106mg, 28%). Compound S6: ¹H NMR (500 MHz, DMSO-d₆) δ 10.06 (s, 1H), 10.05(s, 1H), 8.77 (s, 2H), 7.70-7.30 (m, 6H), 4.32 (s, 2H), 3.37 (bs, 2H),2.96-2.94 (m, 2H), 1.87 (bs, 2H). MS (M+H) 365. Compound S7: ¹H NMR (500MHz, DMSO-d₆) δ 10.02 (s, 1H), 9.94 (s, 1H), 8.85 (s, 2H), 7.70-7.30 (m,6H), 3.22 (bs, 4H), 3.08-2.98 (m, 4H). MS (M+H) 365.

Step 4:2-[3-(4-Chlorophenyl)ureido]-7-ethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepine-3-carboxamide(S8)

To a stirred mixture of compound S6 (185 mg, 0.386 mmol), acetaldehyde(5 M solution in tetrahydrofuran, 0.160 mL, 0.800 mmol), and acetic acid(2 drops) in anhydrous methanol (6 mL) and anhydrous tetrahydrofuran (3mL) at room temperature under nitrogen was added sodium cyanoborohydride(73.0 mg, 1.16 mmol). After addition, the reaction mixture was stirredfor 17 h. After this time, the reaction mixture was diluted withmethylene chloride (100 mL), washed with saturated aqueous sodiumbicarbonate (30 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure. The resulting residue was purifiedby flash column chromatography on silica gel eluting with 20% to 60%methanol/methylene chloride to provide compound S8 as a light yellowsolid (92 mg, 61%): MS (M+H) 393.

Step 5:2-[3-(4-Chlorophenyl)ureido]-7-ethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepine-3-carboxamidehydrochloride (S9)

To a stirred mixture of compound S8 (41.0 mg, 0.104 mmol) in methanol (3mL) and methylene chloride (3 mL) at room temperature was addedhydrochloride (2 M in diethyl ether, 0.100 mL, 0.200 mmol). Afteraddition, the reaction mixture was stirred for 5 min and concentratedunder reduced pressure. The resulting residue was dissolved inacetonitrile (1 mL) and water (1 mL) and lyophilized to provide compoundS9 as an off-white solid (45 mg, 100%): ¹H NMR (500 MHz, DMSO-d₆) δ10.12 (s, 1H), 10.11 (s, 1H), 10.04 (bs, 1H), 7.70-7.30 (m, 6H),4.56-4.40 (m, 2H), 3.59-3.36 (m, 2H), 3.09-2.94 (m, 4H), 2.01-1.84 (m,2H), 1.25 (t, J=7.2 Hz, 3H). MS (M+H) 393.

Example 115: Preparation of2-[3-(4-Chlorophenyl)ureido]-6-ethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 114. MS (M+H) 393. ¹H NMR (500 MHz, DMSO-d₆) δ 10.27 (bs,1H), 10.05 (s, 1H), 10.02 (s, 1H), 7.70-7.25 (m, 6H), 3.60-3.56 (m, 2H),3.25-3.06 (m, 8H), 1.27 (t, J=7.2 Hz, 3H).

Example 116: Preparation of2-[3-(4-Chlorophenyl)ureido]-5-ethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 114. MS (M+H) 379. ¹H NMR (500 MHz, DMSO-d₆) δ 10.58 (s, 1H),10.18 (s, 1H), 9.85 (bs, 1H), 7.65-7.15 (m, 6H), 4.52-3.68 (m, 3H),3.29-3.00 (m, 5H), 1.30 (t, J=7.2 Hz, 3H).

Example 117: Preparation of(+/−)-2-[3-(4-chlorophenyl)ureido]-4a,5,6,7,8,10-hexahydro-4H-thieno[3,2-b]quinolizine-3-carboxamidehydrochloride [(+/−)-T8]

Step 1: 1-(But-3-yn-1-yl)piperidine (T2)

A mixture of piperidine (T1, 2.90 g, 34.0 mmol), potassium carbonate(3.00 g, 21.7 mmol), and 4-bromobut-1-yne (5.00 g, 37.6 mmol) inanhydrous acetonitrile (60 mL) was heated to 80° C. under nitrogen for20 h. After this time, the reaction mixture was cooled to roomtemperature and diluted with water (50 mL). The resulting mixture wasextracted with ethyl acetate (3×50 mL). The combined extracts were driedover anhydrous sodium sulfate, filtered, and concentrated under reducedpressure to afford compound T2 as light brown oil (1.89 g, 40%): MS(M+H) 138.

Step 2: (+/−)-Hexahydro-1H-quinolizin-2(6H)-one [(+/−)-T3]

To a stirred mixture of compound T2 (1.89 g, 13.8 mmol) and 4 Åmolecular sieves (15.5 g) in anhydrous methylene chloride (50 mL) at 0°C. under nitrogen was added 3-chloroperbenzoic acid (mCPBA) (77%, 3.10g, 13.8 mmol). After addition, the reaction mixture was stirred at 0° C.for 1.5 h. After this time, to the reaction mixture was addedtriphenylphosphinegold(I) bis(trifluoromethanesulfonyl)imidate (510 mg,0.690 mmol) and stirred at 0° C. under nitrogen for another 4.5 h. Thereaction mixture was diluted with methylene chloride (100 mL), washedwith 5% aqueous sodium carbonate (2×150 mL), dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure. Theresulting residue was purified by flash column chromatography on silicagel eluting with ammonium hydroxide/methanol/ethyl acetate (0.1:1:10) toafford compound (+/−)-T3 as a brown oil (930 mg, 44%): MS (M+H) 154.

Step 3:(+/−)-2-Amino-4a,5,6,7,8,10-hexahydro-4H-thieno[3,2-b]quinolizine-3-carboxamide[(+/−)-T4] and(+/−)-2-amino-5,5a,6,7,8,9-hexahydro-4H-thieno[3,2-c]quinolizine-3-carboxamide[(+/−)-T5]

A mixture of compound (+/−)-T3 (500 mg, 3.26 mmol), 2-cyanoacetamide(274 mg, 3.26 mmol), sulphur (105 mg, 3.27 mmol), and morpholine (280mg, 3.21 mmol) in ethanol (5 mL) was heated to reflux for 3.5 h undernitrogen. After this time, the reaction mixture was cooled to roomtemperature and concentrated under reduced pressure. The resultingresidue was purified by flash column chromatography on silica geleluting with 4% to 6% methanol/methylene chloride to provide aninseparable isomers (+/−)-T4 and (+/−)-T5 as a brown solid (450 mg,55%): MS (M+H) 252.

Step 4:(+/−)-2-[3-(4-Chlorophenyl)ureido]-4a,5,6,7,8,10-hexahydro-4H-thieno[3,2-b]quinolizine-3-carboxamide[(+/−)-T6] and(+/−)-2-[3-(4-chlorophenyl)ureido]-5,5a,6,7,8,9-hexahydro-4H-thieno[3,2-c]quinolizine-3-carboxamide[(+/−)-T7]

To a stirred mixture of compound (+/−)-T4 and (+/−)-T5 (450 mg, 1.79mmol) in anhydrous N,N-dimethylformamide (9 mL) at room temperatureunder nitrogen was added 4-chlorophenyl isocyanate (275 mg, 1.79 mmol).After addition, the reaction mixture was stirred for 21 h. After thistime, the reaction mixture was concentrated under reduced pressure. Theresulting residue was purified by flash column chromatography on silicagel eluting with 4% to 10% methanol/methylene chloride to providecompound (+/−)-T6 as a yellow solid (110 mg, 15%) and compound (+/−)-T7as a yellow solid (304 mg, 42%). Compound (+/−)-T6: ¹H NMR (500 MHz,DMSO-d₆) δ 10.89 (s, 1H), 10.15 (s, 1H), 7.51-6.45 (m, 6H), 3.10-2.80(m, 2H), 2.60-2.55 (m, 1H), 2.45-2.15 (m, 2H), 1.95-1.25 (m, 8H). MS(M+H) 405. Compound (+/−)-T7: ¹H NMR (500 MHz, DMSO-d₆) δ 10.97 (s, 1H),10.16 (s, 1H), 7.55-6.60 (m, 6H), 3.75-3.65 (m, 1H), 3.15-2.60 (m, 4H),2.20-1.20 (m, 8H). MS (M+H) 405.

Step 5:(+/−)-2-[3-(4-Chlorophenyl)ureido]-4a,5,6,7,8,10-hexahydro-4H-thieno[3,2-b]quinolizine-3-carboxamidehydrochloride [(+/−)-T8]

To a mixture of compound (+/−)-T6 (40 mg, 0.099 mmol) in methanol (2 mL)and methylene chloride (2 mL) was added hydrochloride (2 M in diethylether, 0.099 mL, 0.198 mmol) at room temperature. After addition, thereaction mixture was stirred for 2 min and concentrated under reducedpressure. The resulting residue was triturated with a mixture ofmethanol (0.5 mL), methylene chloride (2 mL), ethyl acetate (5 mL), andhexanes (5 mL) to afford compound (+/−)-T8 as a yellow solid (24 mg,55%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.02 (s, 1H), 10.28 (bs, 2H),7.80-7.00 (m, 6H), 4.50-4.40 (m, 1H), 3.70-3.45 (m, 2H), 3.32-2.95 (m,4H), 2.30-1.55 (m, 6H). MS (M+H) 405.

Example 118: Preparation of(+/−)-2-[3-(4-Chlorophenyl)ureido]-5,7,8,9,10,10a-hexahydro-4H-thieno[2,3-a]quinolizine-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 117. MS (M+H) 405. ¹H NMR (300 MHz, DMSO-d₆) δ 11.04 (s, 1H),10.52 (bs, 1H), 10.29 (s, 1H), 7.90-6.90 (m, 6H), 4.50-4.15 (m, 2H),3.55-3.34 (m, 2H), 3.20-2.88 (m, 3H), 2.10-1.47 (m, 6H).

Example 119: Preparation of2-[3-(4-chlorophenyl)ureido]-6-(2-hydroxy-2-methylpropyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide(U1)

2-[3-(4-Chlorophenyl)ureido]-6-(2-hydroxy-2-methylpropyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide(U1)

A solution of compound A4 (200 mg, 0.430 mmol), 2,2-dimethyloxirane (155mg, 2.15 mmol), and diisopropylethylamine (167 mg, 1.29 mmol) inanhydrous N,N-dimethylformamide (1.5 mL) was stirred at room temperaturefor 2 h and heated to 50° C. in a sealed tube for another 21 h. Afterthis time, the reaction mixture was cooled to room temperature andconcentrated under reduced pressure. The resulting residue was purifiedby flash column chromatography on silica gel eluting with 2% to 6%methanol/methylene chloride to afford compound U1 as a yellow solid (36mg, 20%): ¹H NMR (300 MHz, DMSO-d₆) δ 10.97 (s, 1H), 10.19 (s, 1H),7.70-6.70 (m, 6H), 4.19 (s, 1H), 3.62 (s, 2H), 2.78 (bs, 4H), 2.38 (s,2H), 1.12 (s, 6H). MS (M+H) 423.

Example 120: Preparation of2-[3-(4-chlorophenyl)ureido]-5,5,6,7,7-pentamethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride (V3)

Step 1:2-[3-(4-Chlorophenyl)ureido]-5,5,6,7,7-pentamethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide(V2)

A solution of compound V1 (100 mg, 0.246 mmol), iodomethane (173 mg,1.22 mmol), and diisopropylethylamine (64.0 mg, 0.494 mmol) in anhydrousN,N-dimethylformamide (3 mL) was stirred at room temperature undernitrogen for 90 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The resulting residue was purifiedby flash column chromatography on silica gel eluting with 4% to 12%methanol/methylene chloride to afford compound V2 as an off-white solid(63 mg, 61%): ¹H NMR (300 MHz, DMSO-d₆) δ 10.80 (s, 1H), 10.17 (s, 1H),7.53-6.70 (m, 6H), 2.62 (s, 2H), 2.30 (s, 3H), 1.35 (s, 6H), 1.04 (s,6H). MS (M+Na) 443.

Step 2:2-[3-(4-Chlorophenyl)ureido]-5,5,6,7,7-pentamethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride (V3)

To a stirred solution of compound V2 (63 mg, 0.15 mmol) in methanol (2mL) and methylene chloride (2 mL) was added hydrochloride (2 M indiethyl ether, 0.075 mL, 0.15 mmol). After addition, the reactionmixture was stirred at room temperature for 2 min and concentrated underreduced pressure. The resulting residue was triturated with a mixture ofmethanol (0.5 mL), methylene chloride (2 mL), ethyl acetate (5 mL), andhexanes (5 mL) to afford compound V3 as a white solid (54 mg, 79%): ¹HNMR (300 MHz, DMSO-d₆) δ 10.89 (s, 1H), 10.28 (s, 1H), 10.03 (bs, 1H),7.90-7.00 (m, 6H), 3.27 (s, 1H), 2.92 (s, 1H), 2.85 (s, 3H), 1.78 (s,3H), 1.63 (s, 3H), 1.53 (s, 3H), 1.27 (s, 3H). MS (M+Na) 443.

Example 121: Preparation of2-[3-(4-chlorophenyl)ureido]-6-(methoxyimino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide(W2, isomer A) and W3 (isomer B)

To a stirred solution of compound W1 (100 mg, 0.275 mmol) in anhydrousN,N-dimethylformamide (4 mL) and methanol (10 mL) was added methoxyaminehydrochloride (46.0 mg, 0.551 mmol) followed by sodium acetate (56.0 mg,0.683 mmol). After addition, the reaction mixture was stirred at roomtemperature for 20 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The resulting residue was purifiedby flash column chromatography on silica gel eluting with 30% to 50%ethyl acetate/methylene chloride to afford isomer A W2 as a light yellowsolid (22 mg, 20%) and isomer B W3 as a light yellow solid (35 mg, 32%).Isomer A (W2): ¹H NMR (300 MHz, DMSO-d₆) δ 10.71 (s, 1H), 10.17 (s, 1H),7.65-6.80 (m, 6H), 3.78 (s, 3H), 3.42 (s, 2H), 2.90-2.65 (m, 4H). MS(M+Na) 415. Isomer B (W3): ¹H NMR (300 MHz, DMSO-d₆) δ 10.71 (s, 1H),10.17 (s, 1H), 7.70-6.80 (m, 6H), 3.79 (s, 3H), 3.61 (s, 2H), 2.88-2.85(m, 2H), 2.49-2.45 (m, 2H). MS (M+Na) 415.

Example 122: Preparation of(+/−)-2-[3-(4-chlorophenyl)ureido]-5,6,7,8-tetrahydro-4H-5,8-epiminocyclohepta[b]thiophene-3-carboxamidehydrochloride [(+/−)-X8 and (+/−)-X9, mixture of atropisomers]

Step 1:2-[3-(4-Chlorophenyl)ureido]-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepine-3-carboxamide

A stirred mixture of tert-butyl3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (X1, 2.48 g, 11.0 mmol),2-cyanoacetamide (1.02 g, 12.1 mmol), morpholine (1.92 g, 22.0 mmol),and 4 Å molecular sieves (4.00 g) in ethanol (100 mL) and toluene (60mL) was heated to reflux under nitrogen overnight. After this time, thereaction mixture was cooled to room temperature and filtered. The filtercake was washed with ethanol (30 mL) and filtered. The filtrate wasconcentrated. The resulting residue was purified by a silica gel plugeluting with methanol/methylene chloride (1:9) to provide a partiallypurified product which was used in the subsequent step without furtherpurification (1.10 g): MS (M+H-Boc) 192.

A stirred mixture of the product described above (1.10 g), sulfur (145mg, 4.52 mmol), and morpholine (656 mg, 7.53 mmol) in ethanol (40 mL)was heated to reflux overnight under nitrogen. After this time, thereaction mixture was cooled to room temperature and concentrated underreduced pressure. The resulting residue was mixed with saturated aqueoussodium bicarbonate (30 mL). The resulting aqueous mixture was extractedwith methylene chloride (3×50 mL). The combined organic extracts weredried over anhydrous sodium sulfate, filtered, and concentrated underreduced pressure. The resulting residue was purified by flash columnchromatography on silica gel eluting with ethyl acetate/hexanes (8:2) toprovide an inseparable atropisomers (+/−)-X2 and (+/−)-X3 as a yellowsolid (391 mg, 11%): ¹H NMR (300 MHz, DMSO-d₆) δ 7.02 (bs, 0.25H),6.70-6.40 (m, 3.75H), 5.05 (d, J=5.4 Hz, 0.86H), 4.62 (d, J=5.4 Hz,0.14H), 4.32 (bs, 1H), 3.08-2.94 (m, 1H), 2.30-1.81 (m, 4H), 1.61-1.50(m, 1H), 1.36 and 1.30 (2 s, 9H). MS (M+H) 324.

Step 2: (+/−)-tert-Butyl3-carbamoyl-2-[3-(4-chlorophenyl)ureido]-5,6,7,8-tetrahydro-4H-5,8-epiminocyclohepta[b]thiophene-9-carboxylate[(+/−)-X4, atropisomer A; and (+/−)-X5, atropisomer B]

A stirred mixture of atropisomers (+/−)-X2 and (+/−)-X3 (387 mg, 1.20mmol) in methylene chloride (8 mL) at room temperature under nitrogenwas added 4-chlorophenyl isocyanate (221 mg, 1.44 mmol). After addition,the reaction mixture was stirred overnight and concentrated underreduced pressure. The resulting residue was purified by flash columnchromatography on silica gel eluting with ethyl acetate/hexanes (9:1) toprovide atropisomer A (+/−)-X4 as a pale yellow solid (396 mg, 69%) andatropisomer B (+/−)-X5 as a yellow solid (112 mg, 20%). Atropisomer A[(+/−)-X4]: ¹H NMR (300 MHz, DMSO-d₆) δ 10.59-10.51 (m, 1H), 10.06 (s,1H), 7.51-6.80 (m, 6H), 5.03 (d, J=5.1 Hz, 1H), 4.38 (bs, 1H), 3.19-3.10(m, 1H), 2.29-1.90 (m, 4H), 1.65-1.60 (m, 1H), 1.36 and 1.28 (2 bs, 9H).MS (M−H) 475. Atropisomer B [(+/−)-X5]: ¹H NMR (300 MHz, DMSO-d₆) δ11.09-11.01 (m, 1H), 10.20 (s, 1H), 7.62-6.70 (m, 6H), 4.82 (d, J=5.1Hz, 1H), 4.38 (bs, 1H), 2.15-1.52 (m, 6H), 1.23 (bs, 9H). MS (M−H) 475.

Step 3:(+/−)-2-[3-(4-Chlorophenyl)ureido]-5,6,7,8-tetrahydro-4H-5,8-epiminocyclohepta[b]thiophene-3-carboxamide[(+/−)-X6 and (+/−)-X7, mixture of atropisomers)

To a stirred mixture of atropisomers (+/−)-X4 and (+/−)-X5 (3.5:1) (500mg, 1.05 mmol) in methylene chloride (20 mL) and toluene (3 mL) at roomtemperature under nitrogen was added trifluoroacetic acid (4.60 g, 40.3mmol). After addition, the reaction mixture was stirred for 4 h andconcentrated under reduced pressure. The resulting residue was mixedwith saturated aqueous sodium bicarbonate (30 mL). The resulting aqueousmixture was extracted with 5% methanol/methylene chloride (4×60 mL). Thecombined organic extracts were dried over anhydrous sodium sulfate,filtered, and concentrated under reduced pressure. The resulting residuewas purified by flash column chromatography on silica gel eluting withammonium hydroxide/methanol/methylene chloride (1:14:85) to provide aninseparable atropisomers (+/−)-X6 and (+/−)-X7 (3.5:1) as a white solid(321 mg, 81%): MS (M+H) 377.

Step 4:(+/−)-2-[3-(4-Chlorophenyl)ureido]-5,6,7,8-tetrahydro-4H-5,8-epiminocyclohepta[b]thiophene-3-carboxamidehydrochloride [(+/−)-X8 and (+/−)-X9, mixture of atropisomers]

To a stirred mixture of atropisomers (+/−)-X6 and (+/−)-X7 (3.5:1) (37mg, 0.10 mmol) in methanol at room temperature was added 1 Mhydrochloric acid (2.0 mL, 2.0 mmol). The mixture was sonicated for 20min, diluted with water, and lyophilized to provide a mixture ofatropisomers (+/−)-X8 and (+/−)-X9 (3.5:1) as a white solid (39 mg,96%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.05 (s, 0.18H), 10.29 and 10.28 (2s, 1H), 10.13 (s, 0.82H), 9.52 (bs, 1H), 9.23 and 9.21 (2 s, 0.18H),9.01 and 8.98 (2 s, 0.82H), 7.55-7.20 (m, 6H), 5.00-4.95 (m, 1H), 4.31(bs, 1H), 3.26-3.16 (m, 1H), 2.98-2.72 (m, 1H), 2.28-2.05 (m, 3H),1.84-1.76 (m, 1H). MS (M+H) 377.

Example 123: Preparation of(+/−)-2-[3-(4-Chlorophenyl)ureido]-5,8-dimethyl-5,6,7,8-tetrahydro-4H-5,8-epiminocyclohepta[b]thiophene-3-carboxamidetrifluoroacetate

The title compound was prepared using a similar procedure as describedin Example 122. MS (M+H) 405. ¹H NMR (500 MHz, DMSO-d₆) δ 11.10 (s, 1H),10.28 (s, 1H), 9.40-9.20 (m, 2H), 7.51-7.34 (m, 4H), 6.50 (bs, 2H),3.20-3.05 (m, 2H), 2.25-1.90 (m, 4H), 1.76 (s, 3H), 1.57 (s, 3H).

Example 124: Preparation of(+/−)-2-[3-(4-chlorophenyl)ureido]-5,6,7,8-tetrahydro-4H-5,8-epiminocyclohepta[b]thiophene-3-carboxamidehydrochloride [(+/−)-X9, atropisomer B]

Step 1: (+/−)-tert-Butyl2-amino-3-carbamoyl-5,6,7,8-tetrahydro-4H-5,8-epiminocyclohepta[b]thiophene-9-carboxylate[(+/−)-X3, atropisomer B]

A stirred mixture of tert-butyl3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (X1, 7.50 g, 33.3 mmol),2-cyanoacetamide (2.80 g, 33.3 mmol), 4 Å molecular sieves (8 g), andmorpholine (4.35 g, 49.9 mmol) in ethanol (200 mL) and toluene (200 mL)was heated to reflux under nitrogen with Dean-Stark apparatus to removewater for 2 days. After this time, the reaction mixture was cooled toroom temperature and filtered. The filter cake was washed with ethanol(30 mL). The combined filtrate was concentrated under reduced pressure.The resulting residue was purified by flash column chromatography onsilica gel eluting with methanol/methylene chloride (1:9) to provide anintermediate as a yellow gum (1.67 g, 17%): ¹H NMR (300 MHz, DMSO-d₆) δ7.93 (s, 1H), 7.74 (s, 1H), 4.26 (bs, 1H), 4.17 (bs, 1H), 2.79 (d,J=15.0 Hz, 1H), 2.65-2.50 (m, 2H), 2.40 (d, J=15.0 Hz, 1H), 1.92-1.83(m, 2H), 1.50-1.39 (m, 11H). MS (M−H) 290.

A stirred mixture of the intermediate described above (6.51 g, 22.3mmol), sulfur (931 mg, 29.0 mmol), and morpholine (5.84 g, 67.0 mmol) inethanol (200 mL) was heated to reflux overnight under nitrogen. Afterthis time, the reaction mixture was cooled to room temperature andconcentrated under reduced pressure. The resulting residue was mixedwith saturated aqueous sodium bicarbonate (300 mL) and extracted withmethylene chloride (3×100 mL). The combined organic extracts were driedover anhydrous sodium sulfate, filtered, and concentrated under reducedpressure. The resulting residue was purified by flash columnchromatography on silica gel eluting with ethyl acetate/hexanes (8:2) toprovide atropisomer B (+/−)-X3 as a white solid (6.01 g, 83%): ¹H NMR(300 MHz, DMSO-d₆) δ 7.02 (s, 2H), 6.54 (bs, 2H), 4.62 (d, J=5.1 Hz,1H), 4.30 (bs, 1H), 3.19 (d, J=15.3 Hz, 1H), 2.40-2.39 (m, 1H),2.16-1.82 (m, 3H), 1.63-1.55 (m, 1H), 1.38 (s, 9H). MS (M+H) 324.

Step 2: (+/−)-tert-Butyl3-carbamoyl-2-[3-(4-chlorophenyl)ureido]-5,6,7,8-tetrahydro-4H-5,8-epiminocyclohepta[b]thiophene-9-carboxylate[(+/−)-X5, atropisomer B]

To a stirred mixture of atropisomer (+/−)-X3 (2.00 g, 6.18 mmol) intetrahydrofuran (100 mL) at room temperature under nitrogen was added4-chlorophenyl isocyanate (1.14 g, 7.42 mmol). After addition, thereaction mixture was stirred overnight and concentrated under reducedpressure. The resulting residue was purified by flash columnchromatography on silica gel eluting with ethyl acetate/hexanes (9:1) toprovide atropisomer B (+/−)-X5 as pale yellow solid (2.69 g, 91%): ¹HNMR (300 MHz, DMSO-d₆) δ 11.09-11.01 (m, 1H), 10.20 (s, 1H), 7.62-6.70(m, 6H), 4.82 (d, J=5.1 Hz, 1H), 4.38 (bs, 1H), 2.15-1.52 (m, 6H), 1.23(bs, 9H). MS (M−H) 475.

Step 3:(+/−)-2-[3-(4-Chlorophenyl)ureido]-5,6,7,8-tetrahydro-4H-5,8-epiminocyclohepta[b]thiophene-3-carboxamide[(+/−)-X7, atropisomer B]

To a stirred mixture of atropisomer (+/−)-X5 (2.69 g, 5.64 mmol) inmethylene chloride (50 mL) and toluene (20 mL) at room temperature wasadded trifluoroacetic acid (23.0 g, 202 mmol) dropwise over 5 min. Afteraddition, the reaction mixture was stirred for 2.5 h and thenconcentrated under reduced pressure. The resulting residue was dilutedwith methylene chloride (200 mL) and then slowly quenched with saturatedaqueous sodium bicarbonate (200 mL). The layers were separated and theaqueous layer was extracted with 5% methanol/methylene chloride (4×200mL). The combined organics were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The resulting residue was purifiedby flash column chromatography on silica gel eluting with ammoniumhydroxide/methanol/methylene chloride (1:14:85) to provide atropisomer B(+/−)-X7 as a pale yellow solid (1.43 g, 67%): MS (M+H) 377.

Step 4:(+/−)-2-[3-(4-Chlorophenyl)ureido]-5,6,7,8-tetrahydro-4H-5,8-epiminocyclohepta[b]thiophene-3-carboxamidehydrochloride [(+/−)-X9, atropisomer B]

To a mixture of atropisomer (+/−)-X7 (226 mg, 0.600 mmol) in methanol (5mL) at room temperature was added 1 M hydrochloric acid (1.20 mL, 1.20mmol) dropwise over 2 min. After addition, the mixture was sonicated for0.5 h, diluted with water (10 mL), and lyophilized to provideatropisomer B (+/−)-X9 as a white solid (243 mg, 98%): ¹H NMR (300 MHz,DMSO-d₆) δ 11.05 (s, 1H), 10.30 (s, 1H), 9.73 (bs, 1H), 9.26 and 9.23 (2s, 1H), 7.70-6.75 (m, 6H), 4.94 (bs, 1H), 4.30 (bs, 1H), 3.35-3.27 (m,1H), 3.00-2.91 (m, 1H), 2.26-2.05 (m, 3H), 1.89-1.80 (m, 1H). MS (M+H)377.

Example 125: Preparation of(+/−)-2-[3-(4-chlorophenyl)ureido)-9-methyl-5,6,7,8-tetrahydro-4H-5,8-epiminocyclohepta[b]thiophene-3-carboxamidehydrochloride [(+/−)-Y4]

Step 1:(+/−)-2-Amino-9-methyl-5,6,7,8-tetrahydro-4H-5,8-epiminocyclohepta[b]thiophene-3-carboxamide[(+/−)-Y2]

A stirred mixture of tropinone (Y1, 3.00 g, 21.6 mmol), 2-cyanoacetamide(1.99 g, 23.7 mmol), sulphur (830 mg, 25.9 mmol), and morpholine (3.75g, 43.0 mmol) in ethanol (80 mL) was heated to reflux under nitrogen for4 h. After this time, the reaction mixture was cooled to roomtemperature and concentrated under reduced pressure. The resultingresidue was diluted with saturated aqueous sodium bicarbonate (60 mL)and extracted with methylene chloride (3×150 mL). The combined organicextracts were dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure. The resulting residue was purifiedby flash column chromatography on silica gel eluting withmethanol/methylene chloride (1:9) to provide compound (+/−)-Y2 as abrown solid (396 mg, 8%): MS (M+H) 238.

Step 2:(+/−)-2-[3-(4-Chlorophenyl)ureido]-9-methyl-5,6,7,8-tetrahydro-4H-5,8-epiminocyclohepta[b]thiophene-3-carboxamide[(+/−)-Y3]

To a stirred mixture of compound (+/−)-Y2 (375 mg, 1.58 mmol) inmethylene chloride (10 mL) at room temperature under nitrogen was addeda solution of 4-chlorophenyl isocyanate (255 mg, 1.66 mmol) in methylenechloride (10 mL). The reaction mixture was stirred overnight andconcentrated under reduced pressure. The resulting residue was purifiedby flash column chromatography on silica gel eluting withmethanol/methylene chloride (15:85) to provide compound (+/−)-Y3 as anoff-white solid (369 mg, 60%): ¹H NMR (300 MHz, DMSO-d₆) δ 10.70 (bs,1H), 10.05 (bs, 1H), 7.90-6.50 (m, 6H), 4.11 (bs, 1H), 2.99 (d, J=14.1Hz, 1H), 2.35-1.95 (m, 7H), 1.79 (bs, 1H), 1.48 (bs, 1H). MS (M+H) 391.

Step 3:(+/−)-2-[3-(4-Chlorophenyl)ureido]-9-methyl-5,6,7,8-tetrahydro-4H-5,8-epiminocyclohepta[b]thiophene-3-carboxamidehydrochloride [(+/−)-Y4]

To a mixture of compound (+/−)-Y3 (78 mg, 0.20 mmol) in methanol (3 mL)at 0° C. was added 1 M hydrochloric acid (0.30 mL, 0.30 mmol). Afteraddition, the mixture was stirred for 5 min, diluted with water (6 mL),and lyophilized to provide compound (+/−)-Y4 as a white solid (81 mg,95%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.31 (bs, 0.38H), 10.34 and 10.32 (2s, 1H), 10.22-10.18 (m, 1.62H), 7.60-7.33 (m, 6H), 4.94-4.82 (m, 1H),4.19-4.09 (m, 1H), 3.38-3.16 (m, 1H), 2.86-2.68 (m, 4H), 2.49-2.08 (m,3H), 1.89-1.79 (m, 1H). MS (M+H) 391.

Example 126: Preparation of(+/−)-2-[3-(4-Benzoylphenyl)ureido]-9-methyl-5,6,7,8-tetrahydro-4H-5,8-epiminocyclohepta[b]thiophene-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 125. MS (M+H) 461. ¹H NMR (300 MHz, DMSO-d₆) δ 11.30 (bs,0.37H), 10.53 and 10.50 (2 s, 1H), 10.44 and 10.42 (2 s, 1H), 10.23 (bs,0.63H), 7.80-7.36 (m, 11H), 4.96-4.83 (m, 1H), 4.20-4.09 (m, 1H),3.40-3.18 (m, 1H), 2.89-2.65 (m, 4H), 2.59-2.11 (m, 3H), 1.90-1.81 (m,1H).

Example 127: Preparation of(−)-2-[3-(4-chlorophenyl)ureido]-9-methyl-5,6,7,8-tetrahydro-4H-5,8-epiminocyclohepta[b]thiophene-3-carboxamidehydrochloride [(−)-Z1]

Step 1: Chiral separation of(−)-2-[3-(4-chlorophenyl)ureido]-9-methyl-5,6,7,8-tetrahydro-4H-5,8-epiminocyclohepta[b]thiophene-3-carboxamide[(−)-Y4] and(+)-2-[3-(4-chlorophenyl)ureido]-9-methyl-5,6,7,8-tetrahydro-4H-5,8-epiminocyclohepta[b]thiophene-3-carboxamide[(+)-Y4]

Compound (+/−)-Y4 (720 mg) was separated by chiral preparative HPLC (20μm CHIRALCEL OD, 5 cm×50 cm, 100 mL/min flow rate, 120 mg/injection)eluting with 0.1% diethylamine in 20% ethanol/heptane to provide (−)-Y4as a white solid (268 mg, 37%); followed by (+)-Y4 (250 mg, 35%) as awhite solid. Compound (−)-Y4: MS (M+H) 391. Compound (+)-Y4: MS (M+H)391.

Step 2:(−)-2-[3-(4-Chlorophenyl)ureido]-9-methyl-5,6,7,8-tetrahydro-4H-5,8-epiminocyclohepta[b]thiophene-3-carboxamidehydrochloride [(−)-Z1]

To a stirred mixture of compound (−)-Y4 (240 mg, 0.610 mmol) in methanol(30 mL) at room temperature was added 1 M hydrochloric acid (1.25 mL,1.25 mmol) dropwise. After addition, the mixture was stirred for 10 min.After this time, the mixture was diluted with water (10 mL) andlyophilized to provide compound (−)-Z1 as a white solid (255 mg, 97%):¹H NMR (300 MHz, DMSO-d₆) δ 11.24 (bs, 0.40H), 10.34 and 10.32 (2 s,1H), 10.19-10.16 (m, 1.60H), 7.51-7.48 (m, 4H), 7.35 (d, J=9.0 Hz, 2H),4.95-4.82 (m, 1H), 4.19-4.08 (m, 1H), 3.43-3.17 (m, 1H), 2.88-2.68 (m,4H), 2.45-2.09 (m, 3H), 1.89-1.80 (m, 1H). MS (M+H) 391.

Example 128: Preparation of(+)-2-[3-(4-Chlorophenyl)ureido]-9-methyl-5,6,7,8-tetrahydro-4H-5,8-epiminocyclohepta[b]thiophene-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 127. MS (M+H) 391. ¹H NMR (300 MHz, DMSO-d₆) δ 11.20 (bs,0.34H), 10.34 and 10.31 (2 s, 1H), 10.18 (s, 1H), 10.16 (bs, 0.66H),7.54-7.33 (m, 6H), 4.94-4.90 (m, 1H), 4.20-4.06 (m, 1H), 3.42-3.16 (m,1H), 2.88-2.65 (m, 4H), 2.49-2.28 (m, 2H), 2.21-2.09 (m, 1H), 1.89-1.80(m, 1H).

Example 129: Preparation of(−)-2-[3-(4-Chlorophenyl)ureido]-5,6,7,8-tetrahydro-4H-5,8-epiminocyclohepta[b]thiophene-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 127. MS (M+H) 377. ¹H NMR (300 MHz, DMSO-d₆) δ 11.05 (s, 1H),10.31 (s, 1H), 9.80 (bs, 1H), 9.26 (bs, 1H), 7.80-6.79 (m, 6H), 4.94(bs, 1H), 4.30 (bs, 1H), 3.31 (d, J=15.3 Hz, 1H), 2.96 (d, J=16.5 Hz,1H), 2.29-2.03 (m, 3H), 1.95-1.85 (m, 1H).

Example 130: Preparation of(+)-2-[3-(4-Chlorophenyl)ureido]-5,6,7,8-tetrahydro-4H-5,8-epiminocyclohepta[b]thiophene-3-carboxamidehydrochloride (atropisomer B)

The title compound was prepared using a similar procedure as describedin Example 127. MS (M+H) 377. ¹H NMR (300 MHz, DMSO-d₆) δ 11.04 (m, 1H),10.31 (s, 1H), 9.83 (bs, 1H), 9.28 (bs, 1H), 7.75-6.90 (m, 6H), 4.94 (bs1H), 4.30 (bs, 1H), 3.30-3.12 (m, 1H), 2.99-2.89 (m, 1H), 2.29-2.02 (m,3H), 1.90-1.79 (m, 1H).

Example 131: Preparation of(+/−)-2-[3-(4-chlorophenyl)ureido]-9-(cyclohexylmethyl)-5,6,7,8-tetrahydro-4H-5,8-epiminocyclohepta[b]thiophene-3-carboxamidehydrochloride

Step 1:(+/−)-2-[3-(4-Chlorophenyl)ureido]-9-(cyclohexylmethyl)-5,6,7,8-tetrahydro-4H-5,8-epiminocyclohepta[b]thiophene-3-carboxamide[(+/−)-AA1]

To a stirred mixture of compound (+/−)-X7 (151 mg, 0.401 mmol) inanhydrous tetrahydrofuran (6 mL) and anhydrous N,N-dimethylformamide (2mL) at room temperature under nitrogen was added cyclohexanecarbaldehyde(225 mg, 2.00 mmol) followed with acetic acid (15.0 mg, 0.250 mmol) andanhydrous magnesium sulfate (1 g). The reaction mixture was stirred for10 min. Then to the reaction mixture was added sodiumtriacetoxyborohydride (339 mg, 1.60 mmol) in one portion. The reactionmixture was stirred for another 2 h. After this time, the reaction wasquenched by slow addition of saturated aqueous sodium bicarbonate (20mL). The resulting mixture was filtered through a short silica gel plug.The filter cake was washed with 10% methanol/methylene chloride (3×20mL) and filtered. The layers of the combined filtrate were separated andthe aqueous layer was extracted with methylene chloride (3×30 mL). Thecombined organics were dried over anhydrous sodium sulfate, filtered,and concentrated under reduced pressure. The resulting residue waspurified by flash column chromatography on silica gel eluting withmethanol/methylene chloride (1:9) to provide compound (+/−)-AA1 as awhite solid (128 mg, 68%): ¹H NMR (300 MHz, DMSO-d₆) δ 11.08 (s, 1H),10.17 (s, 1H), 7.51 (dd, J=6.9 and 2.1 Hz, 2H), 7.49 (bs, 1H), 7.33 (dd,J=6.9 and 2.1 Hz, 2H), 6.77 (bs, 1H), 3.85 (d, J=3.9 Hz, 1H), 3.43-3.40(m, 1H), 3.18-3.05 (m, 1H), 2.30-2.21 (m, 3H), 2.09-1.94 (m, 2H),1.80-1.53 (m, 6H), 1.50-1.33 (m, 2H), 1.28-1.06 (m, 3H), 0.89-0.76 (m,2H). MS (M+H) 473.

Step 2:(+/−)-2-[3-(4-Chlorophenyl)ureido)-9-(cyclohexylmethyl)-5,6,7,8-tetrahydro-4H-5,8-epiminocyclohepta[b]thiophene-3-carboxamidehydrochloride [(+/−)-AA2]

To a mixture of compound (+/−)-AA1 (120 mg, 0.250 mmol) in methanol (6mL) at 0° C. was added 1 M hydrochloric acid (0.500 mL, 0.500 mmol). Themixture was stirred for 10 min, diluted with water (10 mL), lyophilizedto provide compound (+/−)-AA2 as a white solid (118 mg, 91%): ¹H NMR(300 MHz, DMSO-d₆) δ 11.06 and 10.84 (2 s, 1H), 10.31 and 10.30 (2 s,1H), 10.24 and 9.88 (2 bs, 1H), 7.70-6.70 (m, 6H), 5.00-4.96 (m, 1H),4.23 (bs, 1H), 3.48-3.38 (m, 1H), 3.16-2.72 (m, 3H), 2.43-2.27 (m, 2H),2.13-2.00 (m, 1H), 1.95-1.55 (m, 7H), 1.32-0.85 (m, 5H). MS (M+H) 473.

Example 132: Preparation of(+/−)-2-[3-(4-Chlorophenyl)ureido]-9-(cyclobutylmethyl)-5,6,7,8-tetrahydro-4H-5,8-epiminocyclohepta[b]thiophene-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 131. MS (M+H) 445. ¹H NMR (300 MHz, DMSO-d₆) δ 10.84 (bs,0.69H), 10.32-9.94 (m, 2.31H), 7.59-7.00 (m, 6H), 4.89-4.78 (m, 1H),4.21-4.12 (m, 1H), 3.25-2.72 (m, 5H), 2.48-1.53 (m, 10H).

Example 133: Preparation of(+/−)-2-[3-(4-Chlorophenyl)ureido]-9-ethyl-5,6,7,8-tetrahydro-4H-5,8-epiminocyclohepta[b]thiophene-3-carboxamidehydrochloride

The title compound was prepared using a similar procedure as describedin Example 131. MS (M+H) 405. ¹H NMR (300 MHz, DMSO-d₆) δ 11.07 (s,0.42H), 10.85 (bs, 0.58H), 10.82 (s, 0.58H), 10.31 and 10.29 (2 s, 1H),10.14 (bs, 0.42H), 7.70-6.86 (m, 6H), 4.98 (bs, 1H), 4.31-4.19 (m, 1H),3.41-3.32 (m, 1H), 3.16-3.00 (m, 3H), 2.38-2.20 (m, 2H), 2.15-2.05 (m,1H), 1.89-1.82 (m, 1H), 1.30-1.21 (m, 3H).

Example 134: Preparation of (+/−)-Methyl3-{3-carbamoyl-2-[3-(4-chlorophenyl)ureido]-5,6,7,8-tetrahydro-4H-5,8-epiminocyclohepta[b]thiophen-9-yl}-2,2-dimethylpropanoatehydrochloride

The title compound was prepared using a similar procedure as describedin Example 131. MS (M+H) 491. ¹H NMR (300 MHz, DMSO-d₆) δ 11.05 (s,0.48H), 10.83 (s, 0.52H), 10.32 and 10.31 (2 s, 1H), 9.79 (bs, 0.52H),9.66 (bs, 0.48H), 7.79-6.85 (m, 6H), 4.95-4.84 (m, 1H), 4.27 (bs, 1H),3.70-3.51 (m, 3H), 3.49-2.86 (m, 4H), 2.55-1.85 (m, 4H), 1.33 and 1.31(2 s, 3H), 1.27 (s, 3H).

Example 135: Preparation of3-carbamoyl-2-[3-(4-chlorophenyl)ureido]-6-isobutyl-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumiodide (BB2)

A solution of compound BB1 (30 mg, 0.074 mmol) and iodomethane (14 mg,0.096 mmol) in N,N-dimethylformamide (1.5 mL) was stirred at roomtemperature for 18 h. After this time, the reaction mixture wasconcentrated under reduced pressure. The resulting residue wastriturated with methylene chloride to afford compound BB2 as a lightyellow solid (27 mg, 68%): ¹H NMR (500 MHz, DMSO-d₆) δ 10.81 (s, 1H),10.26 (s, 1H), 7.80-6.90 (m, 6H), 4.59 (s, 2H), 3.70-3.63 (m, 2H),3.41-3.31 (m, 2H), 3.19-3.12 (m, 2H), 3.10 (s, 3H), 2.36-2.34 (m, 1H),1.08 (d, J=6.8 Hz, 3H), 1.05 (d, J=6.8 Hz, 3H). MS (M) 421.

Example 136: Preparation of3-Carbamoyl-2-[3-(4-chlorophenyl)ureido]-6-ethyl-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumiodide

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 393. ¹H NMR (500 MHz, DMSO-d₆) δ 10.80 (s, 1H),10.26 (s, 1H), 7.72-7.29 (m, 5H), 7.14 (bs, 1H), 4.59-4.52 (m, 2H),3.71-3.58 (m, 2H), 3.51-3.42 (m, 2H), 3.20-3.10 (m, 2H), 3.05 (s, 3H),1.34 (t, J=7.0 Hz, 3H).

Example 137: Preparation of3-Carbamoyl-2-[3-(4-chlorophenyl)ureido]-5-ethyl-5-methyl-5,6-dihydro-4H-thieno[2,3-c]pyrrol-5-iumiodide

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 379. ¹H NMR (500 MHz, DMSO-d₆) δ 11.14 (s, 1H),10.37 (s, 1H), 7.70-6.90 (m, 6H), 5.00-4.97 (m, 1H), 4.88-4.82 (m, 2H),4.73-4.68 (m, 1H), 3.72-3.66 (m, 2H), 3.25 (s, 3H), 1.31 (t, J=7.0 Hz,3H).

Example 138: Preparation of3′-Carbamoyl-2′-[3-(4-chlorophenyl)ureido]-5′,7′-dihydro-4′H-spiro[pyrrolidine-1,6′-thieno[2,3-c]pyridin]-1-iumbromide

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 405. ¹H NMR (500 MHz, DMSO-d₆) δ 10.81 (s, 1H),10.26 (s, 1H), 7.71-6.99 (m, 6H), 4.60 (s, 2H), 3.74-3.69 (m, 2H),3.63-3.50 (m, 4H), 3.22-3.16 (m, 2H), 2.18-2.10 (m, 4H).

Example 139: Preparation of3-Carbamoyl-2-[3-(4-chlorophenyl)ureido]-6,6-diethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumiodide

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 407. ¹H NMR (500 MHz, DMSO-d₆) δ 10.79 (s, 1H),10.26 (s, 1H), 7.80-7.00 (m, 6H), 4.56 (s, 2H), 3.65-3.35 (m, 6H),3.13-3.10 (m, 2H), 1.28 (t, J=7.5 Hz, 6H).

Example 140: Preparation of3-Carbamoyl-2-[3-(4-chlorophenyl)ureido]-6-(cyclopropylmethyl)-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumiodide

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 419. ¹H NMR (500 MHz, DMSO-d₆) δ 10.80 (s, 1H),10.26 (s, 1H), 7.80-7.00 (m, 6H), 4.62 (ABq, J=15.0 Hz, 2H), 3.75-3.41(m, 3H), 3.28-3.12 (m, 6H), 1.26-1.23 (m, 1H), 0.75 (bs, 2H), 0.41 (bs,2H).

Example 141: Preparation of3-Carbamoyl-2-[3-(4-chlorophenyl)ureido]-6-(3-methoxypropyl)-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumiodide

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 437. ¹H NMR (500 MHz, DMSO-d₆) δ 10.81 (s, 1H),10.26 (s, 1H), 7.70-7.00 (m, 6H), 4.65-4.59 (m, 2H), 3.69-3.41 (m, 6H),3.26 (s, 3H), 3.16-3.14 (m, 2H), 3.09 (s, 3H), 2.09-2.02 (m, 2H).

Example 142: Preparation of3-Carbamoyl-2-[3-(4-chlorophenyl)ureido]-6-methyl-6-(oxetan-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumiodide

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 421. ¹H NMR (500 MHz, DMSO-d₆) δ 10.80 (s, 1H),10.27 (s, 1H), 7.80-7.00 (m, 6H), 5.05-4.61 (m, 7H), 3.71-3.58 (m, 2H),3.25-3.08 (m, 5H).

Example 143: Preparation of3-Carbamoyl-2-[3-(4-chlorophenyl)ureido]-6-methyl-6-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumiodide

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 449. ¹H NMR (500 MHz, DMSO-d₆) δ 10.82 (s, 1H),10.27 (s, 1H), 7.80-7.00 (m, 6H), 4.71-4.48 (m, 2H), 4.07-3.35 (m, 7H),3.16 (bs, 2H), 2.98 (s, 3H), 2.14-1.80 (m, 4H).

Example 144: Preparation of3-Carbamoyl-2-[3-(4-chlorophenyl)ureido]-6-(2-hydroxyethyl)-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumiodide

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 409. ¹H NMR (500 MHz, DMSO-d₆) δ 10.82 (s, 1H),10.26 (s, 1H), 7.80-7.00 (m, 6H), 5.35 (s, 1H), 4.65 (ABq, J=15.5 Hz,2H), 3.93-3.49 (m, 6H), 3.18-3.16 (m, 5H).

Example 145: Preparation of3-Carbamoyl-2-[3-(4-chlorophenyl)ureido]-6-(cyclobutylmethyl)-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumiodide

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 433. ¹H NMR (500 MHz, DMSO-d₆) δ 10.80 (s, 1H),10.26 (s, 1H), 7.80-7.00 (m, 6H), 4.51 (s, 2H), 3.65-3.45 (m, 4H), 3.14(bs, 2H), 3.03 (s, 3H), 2.98-2.90 (m, 1H), 2.20-1.70 (m, 6H).

Example 146: Preparation of3′-Carbamoyl-2′-[3-(4-chlorophenyl)ureido]-5′,7′-dihydro-4′H-spiro[morpholine-4,6′-thieno[2,3-c]pyridin]-4-iumiodide

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 421. ¹H NMR (500 MHz, DMSO-d₆) δ 10.80 (s, 1H),10.27 (s, 1H), 7.80-6.90 (m, 6H), 4.80 (s, 2H), 4.15-3.85 (m, 6H),3.58-3.50 (m, 4H), 3.18 (bs, 2H).

Example 147: Preparation of6-(2-tert-Butoxy-2-oxoethyl)-3-carbamoyl-2-[3-(4-chlorophenyl)ureido]-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumiodide

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 479. ¹H NMR (500 MHz, DMSO-d₆) δ 10.79 (s, 1H),10.27 (s, 1H), 7.80-7.00 (m, 6H), 4.74 (ABq, J=16.0 Hz, 2H), 4.38 (s,2H), 3.96-3.74 (m, 2H), 3.29 (s, 3H), 3.19-3.16 (m, 2H), 1.48 (s, 9H).

Example 148: Preparation of3-Carbamoyl-2-[3-(4-chlorobenzyl)ureido]-6-ethyl-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumiodide

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 407. ¹H NMR (500 MHz, DMSO-d₆) δ 10.52 (s, 1H),8.27 (s, 1H), 7.80-6.90 (m, 6H), 4.55-4.45 (m, 2H), 4.28 (s, 2H),3.66-3.43 (m, 4H), 3.11-3.09 (m, 2H), 3.03 (s, 3H), 1.32 (t, J=7.0 Hz,3H).

Example 149: Preparation of3-Carbamoyl-6-(3-carboxypropyl)-2-[3-(4-chlorophenyl)ureido]-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumtrifluoroacetate

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 451. ¹H NMR (500 MHz, DMSO-d₆) δ 12.26 (bs, 1H),10.84 (s, 1H), 10.27 (s, 1H), 7.80-7.00 (m, 6H), 4.60 (s, 2H), 3.70-3.35(m, 4H), 3.15 (bs, 2H), 3.11 (s, 3H), 2.36-1.95 (m, 4H).

Example 150: Preparation of3-Carbamoyl-2-[3-(4-cyanophenyl)ureido]-6-ethyl-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumiodide

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 384. ¹H NMR (500 MHz, DMSO-d₆) δ 9.94 (s, 1H),9.09 (s, 1H), 7.75-7.54 (m, 4H), 6.54 (bs, 1H), 4.41-4.33 (m, 2H),3.60-3.35 (m, 4H), 3.29-3.10 (m, 2H), 3.00 (s, 3H), 1.31 (t, J=7.5 Hz,3H).

Example 151: Preparation of6-(3-tert-Butoxy-3-oxopropyl)-3-carbamoyl-2-[3-(4-chlorophenyl)ureido]-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumiodide

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 493. ¹H NMR (500 MHz, DMSO-d₆) δ 10.81 (s, 1H),10.27 (s, 1H), 7.80-6.90 (m, 6H), 4.60 (ABq, J=16.0 Hz, 2H), 3.75-3.60(m, 4H), 3.17-3.15 (m, 2H), 3.08 (s, 3H), 2.97-2.94 (m, 2H), 1.44 (s,9H).

Example 152: Preparation of3-Carbamoyl-2-[3-(4-chlorophenyl)ureido]-6-(cyclohexylmethyl)-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumiodide

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 461. ¹H NMR (500 MHz, DMSO-d₆) δ 10.81 (s, 1H),10.26 (s, 1H), 7.80-7.00 (m, 6H), 4.58 (s, 2H), 3.75-3.60 (m, 2H),3.28-3.12 (m, 4H), 3.09 (s, 3H), 2.10-1.55 (m, 6H), 1.40-1.00 (m, 5H).

Example 153: Preparation of3-Carbamoyl-2-[3-(4-chlorophenyl)ureido]-6-(cyclopentylmethyl)-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumiodide

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 447. ¹H NMR (500 MHz, DMSO-d₆) δ 10.81 (s, 1H),10.26 (s, 1H), 7.80-7.00 (m, 6H), 4.58 (s, 2H), 3.70-3.46 (m, 4H),3.17-3.14 (m, 2H), 3.10 (s, 3H), 2.42-2.39 (m, 1H), 1.99-1.20 (m, 8H).

Example 154: Preparation of6-(4-tert-Butoxy-4-oxobutyl)-3-carbamoyl-2-[3-(4-chlorophenyl)ureido]-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumtrifluoroacetate

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 507. ¹H NMR (500 MHz, DMSO-d₆) δ 10.83 (s, 1H),10.27 (s, 1H), 7.80-6.90 (m, 6H), 4.59 (s, 2H), 3.68-3.37 (m, 4H),3.16-3.14 (m, 2H), 3.11 (s, 3H), 2.35-1.97 (m, 4H), 1.41 (s, 9H).

Example 155: Preparation of6-(5-tert-Butoxy-5-oxopentyl)-3-carbamoyl-2-[3-(4-chlorophenyl)ureido]-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumiodide

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 521. ¹H NMR (500 MHz, DMSO-d₆) δ 10.80 (s, 1H),10.26 (s, 1H), 7.80-6.90 (m, 6H), 4.56 (s, 2H), 3.70-3.36 (m, 4H), 3.15(bs, 2H), 3.08 (s, 3H), 2.30-2.27 (m, 2H), 1.80-1.50 (m, 4H), 1.41 (s,9H).

Example 156: Preparation of6-(6-tert-Butoxy-6-oxohexyl)-3-carbamoyl-2-[3-(4-chlorophenyl)ureido]-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumiodide

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 535. ¹H NMR (500 MHz, DMSO-d₆) δ 10.81 (s, 1H),10.26 (s, 1H), 7.80-7.00 (m, 6H), 4.60-4.50 (m, 2H), 3.68-3.35 (m, 4H),3.15 (bs, 2H), 3.08 (s, 3H), 2.25-2.22 (m, 2H), 1.78-1.53 (m, 4H), 1.40(s, 9H), 1.32-1.27 (m, 2H).

Example 157: Preparation of6-(3-Amino-3-oxopropyl)-3-carbamoyl-2-[3-(4-chlorophenyl)ureido]-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumiodide

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 436. ¹H NMR (500 MHz, DMSO-d₆) δ 10.80 (s, 1H),10.26 (s, 1H), 7.80-7.00 (m, 8H), 4.63-4.55 (m, 2H), 3.73-3.61 (m, 4H),3.16 (bs, 2H), 3.07 (s, 3H), 2.74-2.69 (m, 2H).

Example 158: Preparation of3-Carbamoyl-2-[3-(4-chlorophenyl)ureido]-6-(4-methoxy-4-oxobutyl)-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumiodide

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 465. ¹H NMR (500 MHz, DMSO-d₆) δ 10.82 (s, 1H),10.26 (s, 1H), 7.80-7.00 (m, 6H), 4.59 (s, 2H), 3.67-3.62 (m, 5H),3.40-3.37 (m, 2H), 3.15 (bs, 2H), 3.11 (s, 3H), 2.47-2.03 (m, 4H).

Example 159: Preparation of3-Carbamoyl-2-[3-(4-chlorophenyl)ureido]-6-(3-isopropoxy-3-oxopropyl)-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumiodide

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 479. ¹H NMR (500 MHz, DMSO-d₆) δ 10.81 (s, 1H),10.27 (s, 1H), 7.80-7.00 (m, 6H), 4.99-4.91 (m, 1H), 4.62 (ABq, J=15.0Hz, 2H), 3.73-3.65 (m, 4H), 3.16 (s, 2H), 3.08 (s, 3H), 3.03-2.99 (m,2H), 1.22 (d, J=6.5 Hz, 6H).

Example 160: Preparation of3-Carbamoyl-2-[3-(4-chlorophenyl)ureido]-6-(3-ethoxy-3-oxopropyl)-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumchloride iodide

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 465. ¹H NMR (500 MHz, DMSO-d₆) δ 10.79 (s, 1H),10.31 (s, 1H), 7.80-7.00 (m, 6H), 4.68-4.59 (m, 2H), 4.13 (q, J=7.0 Hz,2H), 3.74-3.64 (m, 4H), 3.17 (s, 2H), 3.10 (s, 3H), 3.06-3.03 (m, 2H),1.22 (t, J=7.0 Hz, 3H).

Example 161: Preparation of3-Carbamoyl-2-[3-(4-chlorophenyl)ureido]-6-(4-ethoxy-4-oxobutyl)-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumiodide

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 479. ¹H NMR (500 MHz, DMSO-d₆) δ 10.82 (s, 1H),10.26 (s, 1H), 7.80-6.90 (m, 6H), 4.59 (bs, 2H), 4.08 (q, J=7.0 Hz, 2H),3.67-3.37 (m, 4H), 3.15 (bs, 2H), 3.11 (s, 3H), 2.44-2.03 (m, 4H), 1.19(t, J=7.0 Hz, 3H).

Example 162: Preparation of3-Carbamoyl-2-[3-(4-chlorophenyl)ureido]-6,6-dimethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumtrifluoroacetate

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 379. ¹H NMR (500 MHz, DMSO-d₆) δ 10.81 (s, 1H),10.27 (s, 1H), 7.80-6.90 (m, 6H), 4.57 (s, 2H), 3.65-3.63 (m, 2H),3.17-3.15 (m, 8H).

Example 163: Preparation of6-[3-(tert-Butoxycarbonyl)cyclobutyl]-3-carbamoyl-2-[3-(4-chlorophenyl)ureido]-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumiodide

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 519. ¹H NMR (500 MHz, DMSO-d₆) δ 10.79 (s, 1H),10.26 (s, 1H), 7.80-6.90 (m, 6H), 4.55-4.45 (m, 2H), 4.18-3.47 (m, 3H),3.20-3.05 (m, 2H), 3.01 (s, 3H), 2.81-2.59 (m, 3H), 2.43-2.36 (m, 2H),1.43 (s, 9H).

Example 164: Preparation of3-Carbamoyl-2-[3-(4-chlorophenyl)ureido]-6-[3-(isopropylamino)-3-oxopropyl]-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumtrifluoroacetate

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 478. ¹H NMR (500 MHz, DMSO-d₆) δ 10.81 (s, 1H),10.27 (s, 1H), 8.02 (d, J=6.0 Hz, 1H), 7.80-7.00 (m, 6H), 4.59-4.53 (m,2H), 3.87-3.62 (m, 5H), 3.17 (bs, 2H), 3.06 (s, 3H), 2.71-2.65 (m, 2H),1.07 (d, J=6.5 Hz, 6H).

Example 165: Preparation of3-Carbamoyl-2-[3-(4-chlorophenyl)ureido]-6-[4-(dimethylamino)-4-oxobutyl]-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumtrifluoroacetate

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 478. ¹H NMR (500 MHz, DMSO-d₆) δ 10.82 (s, 1H),10.27 (s, 1H), 7.80-6.90 (m, 6H), 4.60 (s, 2H), 3.68-3.15 (m, 6H), 3.11(s, 3H), 2.95 (s, 3H), 2.83 (s, 3H), 2.42-1.98 (m, 4H).

Example 166: Preparation of3-Carbamoyl-2-[3-(4-chlorophenyl)ureido]-6-[4-(isopropylamino)-4-oxobutyl]-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumtrifluoroacetate

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 492. ¹H NMR (500 MHz, DMSO-d₆) δ 10.82 (s, 1H),10.27 (s, 1H), 7.80-6.90 (m, 7H), 4.59 (s, 2H), 3.86-3.38 (m, 5H),3.17-3.15 (m, 2H), 3.10 (s, 3H), 2.15-1.95 (m, 4H), 1.05-1.02 (m, 6H).

Example 167: Preparation of6-(4-Amino-4-oxobutyl)-3-carbamoyl-2-[3-(4-chlorophenyl)ureido]-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumtrifluoroacetate

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 450. ¹H NMR (500 MHz, DMSO-d₆) δ 10.81 (s, 1H),10.27 (s, 1H), 7.80-6.80 (m, 8H), 4.59 (s, 2H), 3.68-3.39 (m, 4H), 3.16(bs, 2H), 3.10 (s, 3H), 2.18-1.95 (m, 4H).

Example 168: Preparation of2-[3-(4-Benzoylphenyl)ureido]-3-carbamoyl-6-ethyl-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumiodide

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 463. ¹H NMR (500 MHz, DMSO-d₆) δ 10.89 (s, 1H),10.59 (s, 1H), 7.80-7.00 (m, 11H), 4.57 (bs, 2H), 3.69-3.44 (m, 4H),3.16 (bs, 2H), 3.06 (s, 3H), 1.34 (t, J=7.0 Hz, 3H).

Example 169: Preparation of3-Carbamoyl-2-[3-(4-chlorophenyl)ureido]-N,N,N-trimethyl-4,5,6,7-tetrahydrobenzo[b]thiophen-6-aminiumiodide

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 407. ¹H NMR (300 MHz, DMSO-d₆) δ 10.94 (s, 1H),10.20 (s, 1H), 7.80-6.70 (m, 6H), 3.76 (bs, 1H), 3.29-2.80 (m, 13H),2.27 (bs, 1H), 1.77-1.74 (m, 1H).

Example 170: Preparation of1-{3-Carbamoyl-2-[3-(4-chlorophenyl)ureido]-4,5,6,7-tetrahydrobenzo[b]thiophen-6-yl}-1-methylazetidin-1-iumiodide

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 419. ¹H NMR (300 MHz, DMSO-d₆) δ 10.94 (s, 1H),10.20 (s, 1H), 7.80-6.70 (m, 6H), 4.67-3.89 (m, 5H), 3.12-2.70 (m, 8H),2.35-1.65 (m, 3H).

Example 171: Preparation of3-Carbamoyl-2-[3-(4-chlorophenyl)ureido]-6-methyl-6-neopentyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumiodide

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 435. ¹H NMR (500 MHz, DMSO-d₆) δ 10.81 (s, 1H),10.26 (s, 1H), 7.80-6.90 (m, 6H), 4.68-4.63 (m, 2H), 3.71-3.67 (m, 2H),3.18-3.09 (m, 7H), 1.18 (s, 9H).

Example 172: Preparation of5-Carbamoyl-6-[3-(4-chlorophenyl)ureido]-2-ethyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-2-iumiodide

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 387. ¹H NMR (500 MHz, DMSO-d₆) δ 9.65 (s, 1H),8.13 (s, 1H), 8.07 (s, 1H), 7.89 (s, 1H), 7.87 (d, J=8.6 Hz, 1H),7.48-7.32 (m, 4H), 7.18 (d, J=8.6 Hz, 1H), 4.55 (s, 2H), 3.70-3.42 (m,4H), 3.15-3.05 (m, 5H), 1.34 (t, J=7.2 Hz, 3H).

Example 173: Preparation of3-Carbamoyl-2-[3-(4-chlorophenyl)ureido]-7-ethyl-7-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepin-7-iumiodide

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 407. ¹H NMR (500 MHz, DMSO-d₆) δ 10.18 (s, 1H),10.12 (s, 1H), 7.75-7.34 (m, 6H), 4.75-4.60 (m, 2H), 3.63 (bs, 2H), 3.27(bs, 1H), 3.05-2.90 (m, 5H), 2.55 (s, 1H), 2.00 (bs, 2H), 1.28 (t, J=7.2Hz, 3H).

Example 174: Preparation of3-Carbamoyl-2-[3-(4-chlorophenyl)ureido]-6-ethyl-6-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepin-6-iumiodide

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 407. ¹H NMR (500 MHz, DMSO-d₆) δ 10.17 (s, 1H),10.06 (s, 1H), 7.80-7.10 (m, 6H), 3.65-3.50 (m, 6H), 3.25-3.09 (m, 7H),1.30 (t, J=7.1 Hz, 3H).

Example 175: Preparation of3-Carbamoyl-6-isobutyl-6-methyl-2-[3-(naphthalen-2-yl)ureido]-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumiodide

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 437. ¹H NMR (300 MHz, DMSO-d₆) δ 10.86 (s, 1H),10.37 (s, 1H), 8.14-7.00 (m, 9H), 4.61 (bs, 2H), 3.75-3.60 (m, 2H),3.29-3.05 (m, 7H), 2.39-2.34 (m, 1H), 1.10-1.04 (m, 6H).

Example 176: Preparation of3-Carbamoyl-6-(cyclobutylmethyl)-6-methyl-2-[3-(naphthalen-2-yl)ureido]-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumiodide

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 449. ¹H NMR (300 MHz, DMSO-d₆) δ 10.85 (s, 1H),10.36 (s, 1H), 8.14-7.00 (m, 9H), 4.53 (bs, 2H), 3.62-3.33 (m, 4H),3.20-2.90 (m, 6H), 2.20-1.75 (m, 6H).

Example 177: Preparation of(+/−)-3-Carbamoyl-2-[3-(4-chlorophenyl)ureido]-9-methyl-4,4a,5,6,7,8,9,10-octahydrothieno[3,2-b]quinolizin-9-iumiodide

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 419. ¹H NMR (300 MHz, DMSO-d₆) δ 10.81 and 10.79(2 s, 1H), 10.28 (s, 1H), 7.80-6.90 (m, 6H), 4.90-4.75 (m, 1H),4.00-3.36 (m, 3H), 3.29-2.90 (m, 5H), 2.20-1.50 (m, 7H).

Example 178: Preparation of(+/−)-3-Carbamoyl-2-[3-(4-chlorophenyl)ureido]-6-methyl-4,5,6,7,8,9,10,10a-octahydrothieno[2,3-a]quinolizin-6-iumchloride

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 419. ¹H NMR (300 MHz, DMSO-d₆) δ 10.85 (s, 1H),10.31 (s, 1H), 7.80-6.90 (m, 6H), 4.65-4.54 (m, 2H), 3.80-3.49 (m, 3H),3.15-2.85 (m, 5H), 2.15-1.50 (m, 6H).

Example 179: Preparation of2-[3-(4-Chlorophenyl)ureido]-6-ethyl-6-methyl-3-(morpholine-4-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumchloride

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 463. ¹H NMR (300 MHz, DMSO-d₆) δ 10.08 (s, 1H),9.70 (s, 1H), 7.51-7.34 (m, 4H), 4.56 (bs, 2H), 3.80-3.35 (m, 12H), 3.03(s, 3H), 2.81 (bs, 2H), 1.33 (t, J=7.0 Hz, 3H).

Example 180: Preparation of3-Carbamoyl-6-ethyl-2-[3-(6-fluoronaphthalen-2-yl)ureido]-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumiodide

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 427. ¹H NMR (300 MHz, DMSO-d₆) δ 10.85 (s, 1H),10.39 (s, 1H), 8.18 (s, 1H), 7.95-7.00 (m, 7H), 4.57 (s, 2H), 3.69-3.55(m, 2H), 3.50-3.41 (m, 2H), 3.20-3.11 (m, 2H), 3.07 (s, 3H), 1.35 (t,J=7.1 Hz, 3H).

Example 181: Preparation of3-Carbamoyl-2-[3-(4-chloronaphthalen-1-yl)ureido]-6-isobutyl-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumiodide

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 471. ¹H NMR (300 MHz, DMSO-d₆) δ 10.90 (s, 1H),10.12 (s, 1H), 8.31-7.11 (m, 8H), 4.59 (s, 2H), 3.67 (bs, 2H), 3.30-3.03(m, 7H), 2.40-2.29 (m, 1H), 1.08 (d, J=7.2 Hz, 3H), 1.05 (d, J=7.2 Hz,3H).

Example 182: Preparation of3-Carbamoyl-2-[3-(4-chloronaphthalen-1-yl)ureido]-6-(cyclobutylmethyl)-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumchloride

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 483. ¹H NMR (300 MHz, DMSO-d₆) δ 10.89 (s, 1H),10.14 (s, 1H), 8.29-8.20 (m, 2H), 7.89-7.14 (m, 6H), 4.52 (s, 2H), 3.62(bs, 2H), 3.46 (bs, 2H), 3.20-2.91 (m, 6H), 2.10-2.07 (m, 2H), 1.98-1.75(m, 4H).

Example 183: Preparation of3-Carbamoyl-2-[3-(4-chloronaphthalen-1-yl)ureido]-6-methyl-6-neopentyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumchloride

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 485. ¹H NMR (300 MHz, DMSO-d₆) δ 10.90 (s, 1H),10.14 (s, 1H), 8.27 (d, J=8.4 Hz, 1H), 8.22 (d, J=8.4 Hz, 1H), 7.87 (d,J=8.1 Hz, 1H), 7.78-7.10 (m, 5H), 4.68 (s, 2H), 3.70 (bs, 2H), 3.40 (bs,2H), 3.25-3.05 (m, 5H), 1.18 (s, 9H).

Example 184: Preparation of3-Carbamoyl-6-ethyl-6-methyl-2-ureido-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumiodide

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 283. ¹H NMR (300 MHz, DMSO-d₆) δ 10.30 (s, 1H),7.92-6.68 (m, 4H), 4.50 (s, 2H), 3.68-3.52 (m, 2H), 3.48-3.40 (m, 2H),3.15-3.10 (m, 2H), 3.04 (s, 3H), 1.32 (t, J=7.2 Hz, 3H).

Example 185: Preparation of3-Carbamoyl-2-[3-(4-chlorophenyl)-3-methylureido]-6-ethyl-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumchloride

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 407. ¹H NMR (300 MHz, DMSO-d₆) δ 11.28 (s, 1H),7.95-6.80 (m, 6H), 4.53 (s, 2H), 3.69-3.51 (m, 2H), 3.26-3.01 (m, 10H),1.31 (bs, 3H).

Example 186: Preparation of(+/−)-3-Carbamoyl-2-[3-(4-chlorophenyl)ureido]-1′,1′-dimethyl-5,7-dihydro-4H-spiro(benzo[b]thiophene-6,2′-pyrrolidin)-1′-iumtrifluoroacetate

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 433. ¹H NMR (300 MHz, DMSO-d₆) δ 10.84 (s, 1H),10.21 (s, 1H), 7.61-6.80 (m, 6H), 3.90-3.45 (m, 2H), 3.27-3.15 (m, 1H),3.06-2.85 (m, 9H), 1.29-1.22 (m, 1H), 2.10-1.85 (m, 5H).

Example 187: Preparation of(+/−)-3-Carbamoyl-2-[3-(4-chlorophenyl)ureido]-9-ethyl-9-methyl-5,6,7,8-tetrahydro-4H-thienocyclohepten-5,8-iminiumchloride

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 419. ¹H NMR (300 MHz, DMSO-d₆) δ 10.30 (s, 1H),10.18 (s, 1H), 7.61-7.40 (m, 4H), 7.36 (d, J=8.7 Hz, 2H), 4.98-4.91 (m,1H), 4.27 (bs, 1H), 3.50-2.95 (m, 9H), 2.25-1.90 (m, 2H), 1.38-1.21 (m,3H).

Example 188: Preparation of(+/−)-3-Carbamoyl-2-[3-(4-chlorophenyl)ureido]-9,9-dimethyl-5,6,7,8-tetrahydro-4H-thienocyclohepten-5,8-iminiumiodide

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 405. ¹H NMR (300 MHz, DMSO-d₆) δ 10.26 (s, 1H),10.08 (s, 1H), 7.65-7.30 (m, 6H), 5.02-4.90 (m, 1H), 4.23 (bs, 1H),3.40-2.96 (m, 8H), 2.65-2.58 (m, 2H), 2.25-2.15 (m, 1H), 2.03-1.93 (m,1H).

Example 189: Preparation of(+/−)-3-Carbamoyl-2-[3-(4-chlorophenyl)ureido]-9-(cyclobutylmethyl)-9-methyl-5,6,7,8-tetrahydro-4H-thienocyclohepten-5,8-iminiumtrifluoroacetate

The title compound was prepared using a similar procedure as describedin Example 135. MS (M) 459. ¹H NMR (300 MHz, DMSO-d₆) δ 10.86 (s,0.24H), 10.33 (s, 0.24H), 10.19 (s, 0.76H), 10.10 (s, 0.76H), 7.55-7.37(m, 4H), 7.36 (d, J=8.7 Hz, 2H), 4.91-4.87 (m, 1H), 4.28-4.18 (m, 1H),3.41-3.22 (m, 3H), 3.10-2.72 (m, 5H), 2.25-0.85 (m, 10H).

Example 190: Preparation of3-carbamoyl-2-[3-(4-chlorophenyl)ureido]-6-(cyclobutylmethyl)-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumchloride (CC2)

A solution of compound CC1 (400 mg, 1.06 mmol) and(bromomethyl)cyclobutane (1.59 g, 10.7 mmol) in N,N-dimethylformamide (5mL) was heated to 80° C. in a sealed tube for 22 h. After this time, thereaction mixture was cooled to room temperature and concentrated underreduced pressure. The resulting residue was purified by flash columnchromatography on silica gel eluting with methanol to 5% ammoniumhydroxide/methanol followed by reverse phase semi-preparative HPLCeluting with 0.05% TFA in acetonitrile/water (gradient from 10% to 100%,Phenomenex Luna column). The product was dissolved in a mixture ofmethanol (2 mL), methylene chloride (5 mL), and hydrochloride (2 M indiethyl ether, 1 mL). The resulting solution was concentrated underreduced pressure to afford compound CC2 as an off-white solid (55 mg,11%): ¹H NMR (500 MHz, DMSO-d₆) δ 10.79 (s, 1H), 10.29 (s, 1H),7.70-6.90 (m, 6H), 4.55-4.45 (m, 2H), 3.61-3.58 (m, 2H), 3.41-3.35 (m,4H), 3.20-3.05 (m, 2H), 2.90-2.80 (m, 1H), 2.20-1.70 (m, 6H), 1.28 (t,J=7.1 Hz, 3H). MS (M) 447.

Example 191: Preparation of3-Carbamoyl-2-[3-(4-chlorophenyl)ureido]-6-isopropyl-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumiodide

The title compound was prepared using a similar procedure as describedin Example 190. MS (M) 407. ¹H NMR (500 MHz, DMSO-d₆) δ 10.80 (s, 1H),10.26 (s, 1H), 7.80-7.00 (m, 6H), 4.66-4.47 (m, 2H), 3.85-3.54 (m, 3H),3.14 (bs, 2H), 2.92 (s, 3H), 1.41-1.36 (m, 6H).

Example 192: Preparation of3-Carbamoyl-2-[3-(4-chlorophenyl)ureido]-6-methyl-6-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumiodide

The title compound was prepared using a similar procedure as describedin Example 190. MS (M) 447. ¹H NMR (500 MHz, DMSO-d₆) δ 10.72 (s, 1H),10.27 (s, 1H), 7.80-7.00 (m, 6H), 4.85-4.62 (m, 4H), 3.89-3.86 (m, 2H),3.36 (s, 3H), 3.27-3.23 (m, 2H).

Example 193: Preparation of3-Carbamoyl-6-methyl-2-(3-naphthalen-2-ylureido)-6-neopentyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumtrifluoroacetate

The title compound was prepared using a similar procedure as describedin Example 190. MS (M) 451. ¹H NMR (500 MHz, DMSO-d₆) δ 10.85 (s, 1H),10.37 (s, 1H), 8.13-7.00 (m, 9H), 4.73-4.64 (m, 2H), 3.71 (bs, 2H), 3.41(s, 2H), 3.20 (bs, 5H), 1.19 (s, 9H).

Example 194: Preparation of3-Carbamoyl-2-[3-(4-chlorophenyl)ureido]-6-[3-(dimethylamino)-3-oxopropyl]-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumchloride

The title compound was prepared using a similar procedure as describedin Example 190. MS (M) 464. ¹H NMR (300 MHz, DMSO-d₆) δ 10.79 (s, 1H),10.34 (s, 1H), 7.80-7.10 (m, 6H), 4.71-4.59 (m, 2H), 3.60-2.93 (m, 14H),2.84 (s, 3H).

Example 195: Preparation of3-Carbamoyl-2-[3-(4-chlorophenyl)ureido]-6-(cyclohexylmethyl)-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumtrifluoroacetate

The title compound was prepared using a similar procedure as describedin Example 190. MS (M) 475. ¹H NMR (500 MHz, DMSO-d₆) δ 10.81 (s, 1H),10.27 (s, 1H), 7.80-7.00 (m, 6H), 4.65-4.56 (m, 2H), 3.70-3.40 (m, 4H),3.28-3.05 (m, 4H), 2.05-1.55 (m, 6H), 1.40-1.05 (m, 8H).

Example 196: Preparation of3-Carbamoyl-2-[3-(4-chlorophenyl)ureido]-6-methyl-6-[(1-methylcyclopropyl)methyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumtrifluoroacetate

The title compound was prepared using a similar procedure as describedin Example 190. MS (M) 433. ¹H NMR (300 MHz, DMSO-d₆) δ 10.80 (s, 1H),10.28 (s, 1H), 7.80-7.00 (m, 6H), 4.70-4.56 (m, 2H), 3.70-3.10 (m, 9H),1.32 (s, 3H), 0.75-0.50 (m, 4H).

Example 197: Preparation of6-[(3r,5r,7r)-Adamantan-1-ylmethyl]-3-carbamoyl-2-[3-(4-chlorophenyl)ureido]-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumchloride

The title compound was prepared using a similar procedure as describedin Example 190. MS (M) 513. ¹H NMR (500 MHz, DMSO-d₆) δ 10.80 (s, 1H),10.28 (s, 1H), 7.80-7.00 (m, 6H), 4.69-4.65 (m, 2H), 3.96 (bs, 2H),3.25-3.12 (m, 7H), 1.99-1.68 (m, 15H).

Example 198: Preparation of6-[4-(tert-Butoxy)-4-oxobutyl]-3-carbamoyl-2-[3-(4-chlorophenyl)ureido]-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumtrifluoroacetate

The title compound was prepared using a similar procedure as describedin Example 190. MS (M) 521. ¹H NMR (500 MHz, DMSO-d₆) δ 10.81 (s, 1H),10.27 (s, 1H), 7.80-7.00 (m, 6H), 4.65-4.56 (m, 2H), 3.75-3.10 (m, 8H),2.38-2.34 (m, 2H), 2.00-1.85 (m, 2H), 1.41 (s, 9H), 1.32 (t, J=7.0 Hz,3H).

Example 199: Preparation of6-[4-(tert-Butoxy)-4-oxobutyl]-3-carbamoyl-2-[3-(4-chlorophenyl)ureido]-6-(cyclobutylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumtrifluoroacetate

The title compound was prepared using a similar procedure as describedin Example 190. MS (M) 561. ¹H NMR (500 MHz, DMSO-d₆) δ 10.84 (s, 1H),10.27 (s, 1H), 7.80-6.90 (m, 6H), 4.54 (s, 2H), 3.65-2.90 (m, 8H),2.40-1.75 (m, 11H), 1.40 (s, 9H).

Example 200: Preparation of3-Carbamoyl-2-[3-(4-chlorophenyl)ureido]-6-ethyl-6-isobutyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumchloride

The title compound was prepared using a similar procedure as describedin Example 190. MS (M) 435. ¹H NMR (500 MHz, DMSO-d₆) δ 10.80 (s, 1H),10.29 (s, 1H), 7.80-7.00 (m, 6H), 4.62 (bs, 2H), 3.66-3.45 (m, 4H),3.29-3.05 (m, 4H), 2.35-2.25 (m, 1H), 1.29 (t, J=7.2 Hz, 3H), 1.08-1.05(m, 6H).

Example 201: Preparation of3-Carbamoyl-2-[3-(4-chlorophenyl)ureido]-6,6-bis(3-hydroxypropyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumchloride

The title compound was prepared using a similar procedure as describedin Example 190. MS (M) 467. ¹H NMR (300 MHz, DMSO-d₆) δ 10.82 (s, 1H),10.31 (s, 1H), 7.80-7.00 (m, 6H), 4.85 (bs, 2H), 4.65 (s, 2H), 3.75-3.35(m, 10H), 3.14 (bs, 2H), 2.00-1.80 (m, 4H).

Example 202: Preparation of3-Carbamoyl-2-[3-(4-chlorophenyl)ureido]-6-(2-hydroxy-2-methylpropyl)-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumiodide

The title compound was prepared using a similar procedure as describedin Example 190. MS (M) 437. ¹H NMR (300 MHz, DMSO-d₆) δ 11.95 (s,0.25H), 11.24 (s, 0.24H), 10.83 (s, 0.72H), 10.29 (s, 0.74H), 7.80-7.00(m, 6H), 5.44-5.42 (m, 1H), 4.87-4.59 (m, 2H), 3.77-3.42 (m, 4H),3.28-3.18 (m, 5H), 1.35-1.33 (m, 6H).

Example 203: Preparation of(+/−)-3-Carbamoyl-2-[3-(4-chlorophenyl)ureido]-6-(1-cyclobutylethyl)-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumchloride

The title compound was prepared using a similar procedure as describedin Example 190. MS (M) 447. ¹H NMR (300 MHz, DMSO-d₆) δ 10.79 (s, 1H),10.32 (s, 1H), 7.80-7.00 (m, 6H), 4.55-4.40 (m, 2H), 3.80-3.50 (m, 3H),3.20-2.80 (6H), 2.15-1.60 (m, 6H), 1.30-1.20 (m, 3H).

Example 204: Preparation of(+/−)-3-Carbamoyl-2-[3-(4-chlorophenyl)ureido]-6-methyl-6-(3-methylbutan-2-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-iumchloride

The title compound was prepared using a similar procedure as describedin Example 190. MS (M) 435. ¹H NMR (300 MHz, DMSO-d₆) δ 10.79 (s, 1H),10.30 (s, 1H), 7.80-7.00 (m, 6H), 4.80-4.39 (m, 2H), 3.90-3.50 (m, 3H),3.90-2.58 (m, 6H), 1.35-0.85 (m, 9H).

Example 205: Preparation of tert-butylN-[3-(3-carbamoyl-2-{[(4-chlorophenyl)carbamoyl]amino}-4H,5H,6H,7H-thieno[2,3-c]pyridin-6-yl)propyl]carbamate(F)

Step 1: tert-Butyl2-amino-3-carbamoyl-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate(B)

A round bottom flask fitted with a stir bar, was charged with sulfur(196 mg, 6.114 mmol) followed by morpholine (704 μL, 8.14 mmol) and thesuspension was stirred at 40° C. for 1 h or until sulfur dissolved inmorpholine. The solution was diluted with anhydrous EtOH, whereupon4-N-Boc-piperidinone (1.20 g, 6.02 mmol) and cyanamide (506 mg, 6.02mmol) were added and the reaction mixture stirred at room temperatureovernight. Upon completion, the reaction mixture was concentrated invacuo to afford viscous orange oil. The resultant product was dilutedwith MeOH and then 10% EtOAc in Hexane was added until precipitation ofthe product was complete. The product was filtered to afford the titlecompound as a tan solid (1.8 g, quantitative yield). ¹H NMR (300 MHz,MeOH-d₄) δ 4.35 (bs, 2H), 3.68-3.55 (m, 2H), 2.71-2.68 (m, 2H), 1.49 (s,9H). LRMS [M+H] 298.

Step 2: tert-Butyl3-carbamoyl-2-[3-(4-chlorophenyl)ureido]-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate(D)

To a stirred solution of 4-chlorophenyl isocyanate (325 mg, 2.12 mmol)and triethylamine (444 μL, 3.18 mmol) in anhydrous THF (10 mL) was addedtert-butyl2-amino-3-carbamoyl-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate(632 mg, 2.12 mmol) and the reaction mixture was stirred at rt for 8 h.The reaction mixture was concentrated in vacuo to afford oil, which wastaken up in DCM and washed with water (×2). The organics were then driedwith anhydrous Na₂SO₄ and concentrated in vacuo. The product waspurified by Isolera system (SiO₂ gel as stationary phase, 25 g HPcolumn, dry loading) using DCM-DCM/MeOH (0%-8% MeOH in DCM) to affordthe title compound as a tan solid (633 mg, 57% yield). LRMS [M+H] 451.

Step 3:2-[3-(4-Chlorophenyl)ureido]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidetrifluoroacetate (E)

A stirred suspension of tert-butyl3-carbamoyl-2-[3-(4-chlorophenyl)ureido]-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate(697 mg, 1.55 mmol) in 6 mL of DCM at rt was treated with 3 mL of TFA.The resultant solution was stirred at rt for 25 min whereupon it wasconcentrated in a rotary evaporator. The product was taken up in MeOHand the solution concentrated in vacuo (×2) to afford the title compoundas a tan solid in quantitative yield. LRMS [M+H] 351.

Step 4: tert-ButylN-[3-(3-carbamoyl-2-{[(4-chlorophenyl)carbamoyl]amino}-4H,5H,6H,7H-thieno[2,3-c]pyridin-6-yl)propyl]carbamate(F)

A solution of2-[3-(4-Chlorophenyl)ureido]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidetrifluoroacetate (0.48 mmol) in anhydrous DMF was treated with triethylamine (200 μL, 1.43 mmol) and N-Boc-bromopropylamine (114 mg, 0.48 mmol)and the reaction mixture was allowed to stir at room temperature for 14h. Analytical HPLC showed close to 50% progression. Another 100 μL oftriethyl amine and 70 mg of N-Boc-bromopropylamine were added and thereaction mixture was stirred at room temperature. Upon completion (48h), DMF was removed under vacuo and the resultant crude mixture wasdiluted with DCM and washed with water (×2). The organic layer was dried(anhydrous Na₂SO₄) and concentrated to afford an oil which was purifiedby flash chromatography Isolera system (SiO₂ gel as stationary phase, 40g HP column, dry loading) using DCM-DCM/MeOH (0%-15% MeOH in DCM) toafford the title compound as a light brown solid (144 mg, 60% yield). ¹HNMR (300 MHz, dmso-d₆) δ 10.95 (s, 1H), 10.18 (s, 1H), 7.55-7.43 (m,2H), 7.37-7.27 (m, 2H), 6.82 (s, 1H), 3.53-3.43 (m, 2H), 3.03-2.90 (m,2H), 2.85-2.57 (m, 4H), 2.50-2.40 (m, 2H), 1.69-1.53 (m, 2H), 1.37 (s,9H). LRMS [M+H] 508.

Example 206: Preparation of tert-ButylN-[3-(3-carbamoyl-2-{[(naphthalen-2-yl)carbamoyl]amino}-4H,5H,6H,7H-thieno[2,3-c]pyridin-6-yl)propyl]carbamate

The title compound was prepared using a similar procedure as describedin Example 205. MS (M+H) 524. ¹H NMR (300 MHz, dmso-d₆) δ 11.00 (s, 1H),10.28 (s, 1H), 8.15 (s, 1H), 7.88-7.76 (m, 3H), 7.56-7.28 (m, 4H), 6.83(s, 1H), 3.55-3.45 (m, 2H), 3.04-2.92 (m, 2H), 2.84-2.60 (m, 4H),2.50-2.40 (m, 2H), 1.68-1.54 (m, 2H), 1.48 (s, 9H).

Example 207: Preparation of tert-Butyl6-[3-(benzyloxy)propyl]-2-{[(4-iodophenyl)carbamoyl]amino}-4H,5H,6H,7H-thieno[2,3-c]pyridine-3-carboxamide

The title compound was prepared using a similar procedure as describedin Example 205. MS (M+H) 591. ¹H NMR (300 MHz, dmso-d₆) δ 10.94 (s, 1H),10.16 (s, 1H), 7.66-7.56 (m, 2H), 7.39-7.23 (m, 7H), 4.45 (s, 2H),3.57-3.40 (m, 3H), 2.84-2.54 (m, 5H), 2.54-2.44 (m, 2H), 1.86-1.71 (m,2H).

Example 208: Preparation of tert-ButylN-[3-(2-{[(4-benzoylphenyl)carbamoyl]amino}-3-carbamoyl-4H,5H,6H,7H-thieno[2,3-c]pyridin-6-yl)propyl]carbamate

The title compound was prepared using a similar procedure as describedin Example 205. MS (M+H) 578.

Example 209: Preparation of2-{[(4-chlorophenyl)carbamoyl]amino}-6-{3-[3-(1H-indol-3-yl)propanamido]propyl}-4H,5H,6H,7H-thieno[2,3-c]pyridine-3-carboxamide

(H)

Step 1:6-(3-aminopropyl)-2-{[(4-chlorophenyl)carbamoyl]amino}-4H,5H,6H,7H-thieno[2,3-c]pyridine-3-carboxamide(G)

A stirred suspension oftert-butyl-N-[3-(2-{[(4-benzoylphenyl)carbamoyl]amino}-3-carbamoyl-4H,5H,6H,7H-thieno[2,3-c]pyridin-6-yl)propyl]carbamate(70 mg, 0.14 mmol) in 4 mL of DCM at rt was treated with 2 mL of TFA.The resultant solution was stirred at rt for 40 min whereupon it wasconcentrated in a rotary evaporator. The product was taken up in MeOHand the solution concentrated in vacuo (×2) to afford the title compoundas a light tan solid in quantitative yield. LRMS [M+H] 408.

Step 2:2-{[(4-chlorophenyl)carbamoyl]amino}-6-{3-[3-(1H-indol-3-yl)propanamido]propyl}-4H,5H,6H,7H-thieno[2,3-c]pyridine-3-carboxamide(H)

To a stirred solution of6-(3-aminopropyl)-2-{[(4-chlorophenyl)carbamoyl]amino}-4H,5H,6H,7H-thieno[2,3-c]pyridine-3-carboxamide(0.14 mmol) in anhydrous THF (1.5) were added triethyl amine (93 μL,0.66 mmol), 3-indolepropionic acid (31 mg, 0.16 mmol), EDC.HCl (31 mg,0.16 mmol), HOBt (25 mg, 0.16 mmol) and the resultant mixture wasstirred at room temperature for 8 h. Upon completion, the solvent wasremoved in vacuo and the oil was taken up in DCM. The organics werewashed with water (×2) and dried (anhydrous Na₂SO₄) and evaporated toafford the crude product which was purified by flash chromatographyIsolera system (SiO₂ gel as stationary phase, 12 g HP column, dryloading) using DCM-DCM/MeOH (0%-12% MeOH in DCM) to afford the titlecompound as a brown solid (31 mg, 37% yield). ¹H NMR (300 MHz, MeOH-d₄)δ 7.55 (d, J=15.5 Hz, 1H), 7.50-7.43 (m, 2H), 7.34-7.24 (m, 3H),7.12-6.95 (m, 3H), 3.38 (bs, 2H), 3.17 (t, J=6.7 Hz, 2H), 3.06 (t, J=7.2Hz, 2H), 2.82-2.74 (m, 2H), 2.68-2.61 (m, 2H), 2.55 (t, J=7.2 Hz, 2H),2.36-2.27 (m, 2H), 1.67-1.54 (m, 2H). LRMS [M+H] 579.

Example 210: Preparation of2-{[(4-chlorophenyl)carbamoyl]amino}-6-[3-(3-phenylpropanamido)propyl]-4H,5H,6H,7H-thieno[2,3-c]pyridine-3-carboxamide

The title compound was prepared using a similar procedure as describedin Example 209. MS (M+H) 540. ¹H NMR (300 MHz, dmso-d₆) δ 10.94 (s, 1H),10.33 (s, 1H), 8.15 (s, 1H), 7.51 (d, J=8.8 Hz, 2H), 7.35 (d, J=8.8 Hz,2H), 7.31-7.13 (m, 5H), 4.47 (d, J=14.4 Hz, 1H), 4.18 (d, J=13.4 Hz,1H), 3.63-3.23 (m, 4H), 3.18-2.98 (m, 5H), 2.78-2.76 (m, 2H), 2.45-2.31(m, 2H), 1.95-1.87 (m, 2H).

Example 211: Preparation of2-{[(4-chlorophenyl)carbamoyl]amino}-6-{3-[3-(pyridin-3-yl)propanamido]propyl}-4H,5H,6H,7H-thieno[2,3-c]pyridine-3-carboxamide

The title compound was prepared using a similar procedure as describedin Example 209. MS (M+H) 541.

Example 212: Preparation of2-{[(4-chlorophenyl)carbamoyl]amino}-6-[3-(phenylformamido)propyl]-4H,5H,6H,7H-thieno[2,3-c]pyridine-3-carboxamide

The title compound was prepared using a similar procedure as describedin Example 209. MS (M+H) 512. ¹H NMR (300 MHz, MeOH-d₄) δ 7.82-7.74 (m,2H), 7.54-7.36 (m, 5H), 7.31-7.18 (m, 2H), 3.85 (bs, 2H), 3.54-3.45 (m,2H), 3.11-2.83 (m, 6H), 2.05-1.94 (m, 2H).

Example 213: Preparation of6-{3-[3-(4-tert-butylphenyl)propanamido]propyl}-2-{[(4-chlorophenyl)carbamoyl]amino}-4H,5H,6H,7H-thieno[2,3-c]pyridine-3-carboxamide

The title compound was prepared using a similar procedure as describedin Example 209. MS (M+H) 596. ¹H NMR (300 MHz, MeOH-d₄) δ 7.52-7.43 (m,2H), 7.36-7.23 (m, 4H), 7.15-7.06 (m, 2H), 3.61 (bs, 2H), 3.27-3.15 (m,2H), 2.93-2.78 (m, 5H), 2.62-2.52 (m, 2H), 2.50-2.39 (m, 2H), 1.82-1.66(m, 2H), 1.26 (s, 9H).

Example 214: Preparation of2-{[(4-chlorophenyl)carbamoyl]amino}-6-{3-[3-(naphthalen-1-yl)propanamido]propyl}-4H,5H,6H,7H-thieno[2,3-c]pyridine-3-carboxamide

The title compound was prepared using a similar procedure as describedin Example 209. MS (M+H) 590. ¹H NMR (300 MHz, MeOH-d₄) δ 8.13-8.04 (m,1H), 7.88-7.81 (m, 1H), 7.75-7.68 (m, 1H), 7.57-7.22 (m, 8H), 3.52 (bs,2H), 3.42-3.33 (m, 2H), 3.18 (t, J=6.6 Hz, 2H), 2.87-2.72 (m, 4H),2.65-2.56 (m, 2H), 2.48-2.40 (m, 2H), 1.73-1.59 (m, 2H).

Example 215: Preparation of2-{[(4-chlorophenyl)carbamoyl]amino}-6-[3-(cyclopropylformamido)propyl]-4H,5H,6H,7H-thieno[2,3-c]pyridine-3-carboxamide

The title compound was prepared using a similar procedure as describedin Example 209. MS (M+H) 488.

Example 216: Preparation of2-{[(4-chlorophenyl)carbamoyl]amino}-6-[3-(pent-4-ynamido)propyl]-4H,5H,6H,7H-thieno[2,3-c]pyridine-3-carboxamide

The title compound was prepared using a similar procedure as describedin Example 209. MS (M+H) 488.

Example 217: Preparation of2-{[(4-chlorophenyl)carbamoyl]amino}-6-{3-[(2E)-3-phenylprop-2-enamido]propyl}-4H,5H,6H,7H-thieno[2,3-c]pyridine-3-carboxamide

The title compound was prepared using a similar procedure as describedin Example 209. MS (M+H) 538. ¹H NMR (300 MHz, dmso-d₆) δ 10.95 (s, 1H),10.26 (s, 1H), 9.85 (s, 1H), 8.35 (s, 1H), 7.61-7.27 (m, 10H), 6.64 (d,J=15.8 Hz, 1H), 3.32-3.25 (m, 3H), 3.14-2.96 (m, 7H), 2.00-1.78 (m, 2H).

Example 218: Preparation of2-{[(4-chlorophenyl)carbamoyl]amino}-6-(3-{3-[4-(trifluoromethyl)phenyl]propanamido}propyl)-4H,5H,6H,7H-thieno[2,3-c]pyridine-3-carboxamide

The title compound was prepared using a similar procedure as describedin Example 209. MS (M+H) 608.

Example 219: Preparation of6-butyl-3-carbamoyl-2-{[(4-chlorophenyl)carbamoyl]amino}-6-methyl-4H,5H,6H,7H-thieno[2,3-c]pyridin-6-ium

A stirred solution of6-butyl-2-(3-(4-chlorophenyl)ureido)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide(16.0 mg, 0.04 mmol) in anhydrous THF was treated with MeI (2.4 μL, 0.4mmol) and the reaction mixture was heated at 45° C. Upon completion, asjudged by LC-MS, the solvent was removed under vacuo. The resultantsolid was washed with DCM and the washings were discarded. The remainingsolid was diluted with MeOH and the reaction mixture concentrated (×2)to afford the title compound as a light brown solid in quantitativeyield. MS (M) 421.

Example 220: Preparation of2-{[(4-bromophenyl)carbamoyl]amino}-3-carbamoyl-6-ethyl-6-methyl-4H,5H,6H,7H-thieno[2,3-c]pyridin-6-ium

The title compound was prepared using a similar procedure as describedin Example 219. MS (M) 439.

Example 221: Preparation of6-ethyl-2-({[4-(trifluoromethyl)phenyl]carbamoyl}amino)-4H,5H,6H,7H-thieno[2,3-c]pyridine-3-carboxamide

A vigorously stirred solution of 4-trifluoromethyl aniline (161 mg, 1.0mmol) in DCM (3 mL) at room temperature was treated with aq. NaHCO₃ (3mL) and triphosgene (98 mg, 0.33 mmol) and the reaction mixture wasvigorously stirred at room temperature for 45 min.2-Amino-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide(225 mg, 1.0 mmol) was next added followed by THF and the reactionmixture was stirred at room temperature for 8 h. The solvent was thenremoved under vacuo and the resultant crude product was diluted withmethanol and the insoluble solid was filtered off. Upon evaporation ofMeOH, the crude oil was taken up in DCM and washed with water (×2), andthe aqueous layer was back extracted with DCM. All organics werecombined, dried (Na₂SO₄) and concentrated using a rotary evaporator. Thecrude product was purified by flash chromatography, Isolera system (SiO₂gel as stationary phase, 12 g HP column, dry loading) using DCM-DCM/MeOH(0%-10% MeOH in DCM) to afford the title compound as a brown solid (128mg, 31% yield). MS (M+H) 413.

Example 222: Preparation of2-{[(4-bromophenyl)carbamoyl]amino}-6-ethyl-4H,5H,6H,7H-thieno[2,3-c]pyridine-3-carboxamide

The title compound was prepared using a similar procedure as describedin Example 221. MS (M+H) 423.

Example 223: Preparation of6-ethyl-2-{[(naphthalen-2-yl)carbamoyl]amino}-4H,5H,6H,7H-thieno[2,3-c]pyridine-3-carboxamide

The title compound was prepared using a similar procedure as describedin Example 221. MS (M+H) 395. ¹H NMR (300 MHz, dmso-d₆) δ 11.00 (s, 1H),10.26 (s, 1H), 8.78-8.18 (s, 1H), 7.87-7.74 (m, 3H), 7.67-7.31 (m, 4H),3.31-3.41 (m, 2H), 2.83-2.72 (m, 7H), 2.70-2.60 (m, 2H), 2.58-2.48 (m,2H), 1.08 (t, J=7.1 Hz, 2H).

Example 224: Preparation of6-ethyl-2-{[(4-iodophenyl)carbamoyl]amino}-4H,5H,6H,7H-thieno[2,3-c]pyridine-3-carboxamide

The title compound was prepared using a similar procedure as describedin Example 221. MS (M+H) 471. ¹H NMR (300 MHz, dmso-d₆) δ 10.95 (s, 1H),10.16 (s, 1H), 7.60 (d, J=8.8 Hz, 2H), 7.32 (t, J=8.8 Hz, 2H), 7.67-7.31(m, 4H), 3.61-3.39 (m, 2H), 2.88-2.63 (m, 4H), 2.61-2.45 (m, 2H), 1.08(t, J=7.1 Hz, 2H).

Example 225: Preparation of6-ethyl-2-{[(4-phenoxyphenyl)carbamoyl]amino}-4H,5H,6H,7H-thieno[2,3-c]pyridine-3-carboxamide

The title compound was prepared using a similar procedure as describedin Example 221. MS (M+H) 437.

Example 226: Preparation of2-{[(4-benzylphenyl)carbamoyl]amino}-6-ethyl-4H,5H,6H,7H-thieno[2,3-c]pyridine-3-carboxamide

The title compound was prepared using a similar procedure as describedin Example 221. MS (M+H) 435.

Example 227: Preparation of6-ethyl-2-{[(5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]amino}-4H,5H,6H,7H-thieno[2,3-c]pyridine-3-carboxamide

The title compound was prepared using a similar procedure as describedin Example 221. MS (M+H) 399.

Example 228: Preparation of2-{[(4-chloronaphthalen-1-yl)carbamoyl]amino}-6-ethyl-4H,5H,6H,7H-thieno[2,3-c]pyridine-3-carboxamide

The title compound was prepared using a similar procedure as describedin Example 221. MS (M+H) 430. ¹H NMR (300 MHz, dmso-d₆) δ 10.99 (s, 1H),10.18 (s, 1H), 8.32-8.15 (m, 2H), 7.92-7.81 (m, 1H), 7.77-7.64 (m, 3H),3.54-3.40 (m, 2H), 2.84-2.59 (m, 4H), 2.58-2.45 (m, 2H), 1.08 (t, J=7.1Hz, 2H).

Example 229: Preparation of2-{[(2,4-dichlorophenyl)carbamoyl]amino}-6-ethyl-4H,5H,6H,7H-thieno[2,3-c]pyridine-3-carboxamide

The title compound was prepared using a similar procedure as describedin Example 221. MS (M+H) 413.

Example 230: Preparation of6-ethyl-2-{[(4-methoxyphenyl)carbamoyl]amino}-4H,5H,6H,7H-thieno[2,3-c]pyridine-3-carboxamide

The title compound was prepared using a similar procedure as describedin Example 221. MS (M+H) 375.

Example 231: Hair Cell Toxicity Assay in Zebrafish

Zebrafish are bred and newly fertilized embryos are collected the weekprior and raised at 28.5° C. in petri dishes containing embryo medium.Newly hatched free-swimming larvae are fed paramecium and dry fish foodat 4 days post fertilization (dpf) with lights on. For treatment, fish5-7 dpf are transferred to cell culture baskets and place within a wellof a 6-well plate containing 7 milliliters of 1× embryo medium.Typically, tests are done with ten fish per basket but work well with upto 50 fish. All treatment and wash volumes are 7 milliliters.

1. Fish are pre-treated with test compound for 1 hour. Concentrationsbetween 0.010 to 25 micromolar of test compound are tested.

2. Treat with 200 micromolar neomycin (neomycin sulfate, Sigma, St.Louis, Mo., catalog #N1142)+test compound for 30 minutes.

3. Rinse fish briefly 4 times in embryo medium and add 700 μl of 0.05%DASPEI (2-{4-(dimethylamino)styryl}-N-ethylpyridinium iodide, MolecularProbes, Eugene, Oreg.) and allowed to stain for 15 minutes.

4. Rinse twice in embryo medium and add 350 μl MS222 (0.55 ug/ml finalconcentration, 3-aminobenzoic acid ethyl ester, methansulfoneate salt,Sigma, St. Louis, Mo.) to anesthetize.

5. View with epifluorescence dissecting microscope equipped with aDAPSEI filter set (excitation 450-490 nM and barrier 515 nM, ChromaTechnologies, Brattleboro, Vt.). For assessment of initial dose responsecurves, fish are transferred to wide depression slide with wide-borepipette. The DASPEI staining of ten neuromasts (SO1, SO2, IO1, IO2, IO3,IO4, M2, MI1, MI2 and O2) on one side of an animal are evaluated. Eachneuromast is scored for presence of DASPEI staining (score=2), reducedDASPEI staining (score=1) or absence of DASPEI staining (score=0). Totalscores for an animal are tabulated, to give a composite score that canrange from 0 to 20. Average scores and standard deviations arecalculated for animals in each treatment group. Scores are normalized tocontrol group (vehicle only, no drug, no neomycin) and expressed as %hair cell survival. HCmax is the maximum protection (hair cell survival)observed.6. If at least 50% hair cells survive, the HC50 (concentration thatwould produce 50% hair cell survival) is calculated as a linearextrapolation from the nearest concentrations of protective drug thatproduce hair cell survival below and above 50%. If less than 50% haircells survive, the HC50 is not determined.1× embryo media (standard lab EM):1 mM MgSO₄,0.15 mM KH₂PO₄,0.05 mM Na₂HPO₄,1 mM CaCl₂,0.5 mM KCl15 mM NaCl0.7 mM NaHCO₃

TABLE 1 Max HC Max HC Example HC₅₀ (μM) Protection Example HC₅₀ (μM)Protection 1 B 92% @ 25 μM 2 B 84% @ 25 μM 3 B 76% @ 25 μM 4 B 56% @ 8.3μM 5 B 89% @ 8.3 μM 6 B 72% @ 25 μM 7 B 78% @ 25 μM 8 C 84% @ 25 μM 9 B82% @ 25 μM 10 ND 13% @ 8.3 μM 11 B 68% @ 25 μM 12 B 73% @ 8.3 μM 13 ND17% @ 8.3 μM 14 A 83% @ 8.3 μM 15 C 57% @ 25 μM 16 B 57% @ 2.8 μM 17 B65% @ 8.3 μM 18 A 64% @ 2.8 μM 19 A 68% @ 8.3 μM 20 B 65% @ 25 μM 21 B57% @ 2.8 μM 22 ND 22% @ 2.8 μM 23 ND 43% @ 2.8 μM 24 B 54% @ 2.8 μM 25B 57% @ 2.8 μM 26 B 68% @ 8.3 μM 27 B 79% @ 25 μM 28 B 58% @ 8.3 μM 29 B75% @ 25 μM 30 B 58% @ 25 μM 31 ND 22% @ 25 μM 32 ND 19% @ 25 μM 33 ND9% @ 0.93 μM 34 B 87% @ 25 μM 35 ND 42% @ 2.8 μM 36 ND 13% @ 8.3 μM 37 B105% @ 25 μM 38 ND 14% @ 2.8 μM 39 C 56% @ 25 μM 40 B 62% @ 8.3 μM 41 ND39% @ 8.3 μM 42 B 90% @ 25 μM 43 B 93% @ 25 μM 44 B 98% @ 25 μM 45 B 78%@ 25 μM 46 C 79% @ 25 μM 47 A 73% @ 2.8 μM 48 B 72% @ 25 μM 49 B 64% @2.8 μM 50 B 82% @ 25 μM 51 B 55% @ 8.3 μM 52 ND 33% @ 25 μM 53 B 103% @25 μM 54 B 58% @ 25 μM 55 ND 17% @ 2.8 μM 56 ND 48% @ 2.8 μM 57 B 50% @2.8 μM 58 ND 7% @ 2.8 μM 59 ND 40% @ 8.3 μM 60 B 71% @ 25 μM 61 ND 24% @25 μM 62 ND 29% @ 25 μM 63 B 54% @ 2.8 μM 64 B 77% @ 25 μM 65 ND 17% @2.8 μM 66 C 57% @ 25 μM 67 ND 20% @ 8.3 μM 68 ND 5% @ 25 μM 69 ND 12% @25 μM 70 B 64% @ 25 μM 71 ND 45% @ 25 μM 72 B 68% @ 25 μM 73 C 51% @ 25μM 74 C 54% @ 25 μM 75 ND 24% @ 25 μM 76 ND 40% @ 25 μM 77 ND 45% @ 25μM 78 C 52% @ 25 μM 79 ND 34% @ 0.3 μM 80 ND 36% @ 8.3 μM 81 ND 32% @8.3 μM 82 ND 23% @ 25 μM 83 B 63% @ 25 μM 84 ND 4% @ 25 μM 85 B 63% @ 25μM 86 B 51% @ 8.3 μM 87 ND 11% @ 25 μM 88 B 88% @ 25 μM 89 ND 18% @ 8.3μM 90 B 99% @ 8.3 μM 91 ND 15% @ 0.9 μM 92 ND 22% @ 2.8 μM 93 B 97% @ 25μM 94 C 69% @ 25 μM 95 B 78% @ 25 μM 96 B 57% @ 8.3 μM 97 ND 37% @ 8.3μM 98 C 52% @ 25 μM 99 ND 18% @ 2.8 μM 100 B 59% @ 25 μM 101 B 74% @ 25μM 102 ND 22% @ 25 μM 103 ND 12% @ 0.9 μM 104 ND 0% @ 25 μM 105 ND 7% @25 μM 106 ND 23% @ 25 μM 107 ND 36% @ 2.8 μM 108 ND 13% @ 0.9 μM 109 ND22% @ 25 μM 110 C 69% @ 25 μM 111 B 55% @ 2.8 μM 112 ND 49% @ 25 μM 113ND 12% @ 2.8 μM 114 B 97% @ 25 μM 115 B 99% @ 25 μM 116 B 82% @ 25 μM117 B 78% @ 25 μM 118 B 99% @ 25 μM 119 B 65% @ 25 μM 120 B 81% @ 2.8 μM121 ND 6% @ 03 μM 122 A 91% @ 25 μM 123 A 60% @ 2.8 μM 124 A 91% @ 25 μM125 A 99% @ 8.3 μM 126 ND 41% @ 2.8 μM 127 B 55% @ 2.8 μM 128 A 93% @2.8 μM 129 A 81% @ 2.8 μM 130 ND 40% @ 2.8 μM 131 A 88% @ 2.8 μM 132 A97% @ 2.8 μM 133 A 76% @ 25 μM 134 ND 11% @ 0.9 μM 135 A 107% @ 25 μM136 B 76% @ 25 μM 137 B 85% @ 25 μM 138 A 94% @ 25 μM 139 A 99% @ 25 μM140 A 92% @ 25 μM 141 A 77% @ 2.8 μM 142 B 82% @ 25 μM 143 B 96% @ 25 μM144 B 78% @ 25 μM 145 A 95% @ 8.3 μM 146 B 96% @ 25 μM 147 A 90% @ 2.8μM 148 C 51% @ 25 μM 149 ND 24% @ 25 μM 150 ND 43% @ 25 μM 151 A 105% @2.8 μM 152 A 78% @ 0.9 μM 153 A 98% @ 8.3 μM 154 A 96% @ 2.8 μM 155 A75% @ 2.8 μM 156 A 96% @ 2.8 μM 157 B 94% @ 25 μM 158 B 80% @ 25 μM 159A 84% @ 2.8 μM 160 B 70% @ 2.8 μM 161 A 87% @ 2.8 μM 162 ND 36% @ 2.8 μM163 A 88% @ 8.3 μM 164 B 60% @ 2.8 μM 165 B 52% @ 2.8 μM 166 B 63% @ 2.8μM 167 ND 21% @ 2.8 μM 168 ND 20% @ 2.8 μM 169 B 101% @ 25 μM 170 B 85%@ 25 μM 171 A 92% @ 2.8 μM 172 C 66% @ 25 μM 173 B 102% @ 25 μM 174 B74% @ 25 μM 175 A 111% @ 25 μM 176 A 100% @ 8.3 μM 177 B 97% @ 25 μM 178B 102% @ 25 μM 179 ND 38% @ 8.3 μM 180 B 102% @ 25 μM 181 B 93% @ 25 μM182 B 76% @ 83 μM 183 B 70% @ 8.3 μM 184 ND 30% @ 25 μM 185 ND 16% @ 2.8μM 186 A 65% @ 2.8 μM 187 B 72% @ 25 μM 188 B 59% @ 25 μM 189 B 96% @ 25μM 190 A 100% @ 2.8 μM 191 A 80% @ 8.3 μM 192 A 88% @ 25 μM 193 A 98% @25 μM 194 ND 36% @ 2.8 μM 195 A 74% @ 0.9 μM 196 A 85% @ 2.8 μM 197 A93% @ 2.8 μM 198 A 89% @ 2.8 μM 199 A 68% @ 0.3 μM 200 A 97% @ 2.8 μM201 A 102% @ 2.5 μM 202 A 85% @ 8.3 μM 203 A 75% @ 2.8 μM 204 ND 77% @8.3 μM 205 B 81% @ 6.3 μM 206 B 88% @ 6.3 μM 207 B 66% @ 25 μM 208 B 56%@ 2.8 μM 209 A 98% @ 2.8 μM 210 A 99% @ 25 μM 211 A 95% @ 25 μM 212 B103% @ 25 μM 213 A 92% @ 2.8 μM 214 A 95% @ 2.8 μM 215 B 95% @ 25 μM 216B 97% @ 25 μM 217 A 93% @ 2.8 μM 218 A 103% @ 2.8 μM 219 A 92% @ 25 μM220 A 98% @ 25 μM 221 B 68% @ 25 μM 222 B 90% @ 25 μM 223 B 104% @ 25 μM224 B 94% @ 12.5 μM 225 B 91% @ 25 μM 226 B 68% @ 8.3 μM 227 B 80% @ 25μM 228 B 93% @ 25 μM 229 C 54% @ 25 μM 230 ND 48% @ 25 μM A: HC50 <1 μM;B: 1 μM ≦ HC50 ≦ 10 μM; C: HC50 >10 μM; ND: not determined.

Example 232: Hair Cell Toxicity Assay in Zebrafish Treated with VariousAminoglycoside Antibiotics

The assay is performed as described in Example 231 with neomycin (FIG.1), substituting neomycin with amikacin (FIG. 2), substituting neomycinwith streptomycin (FIG. 3), substituting neomycin with gentamicin (FIG.4), and substituting neomycin with kanamycin (FIG. 5), using PROTO-1(2-(3-(4-chlorophenyl)ureido)-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide)as the test compound and varying the concentrations of theaminoglycoside antibiotic.

Example 233: Clinical Trial of the Protective Effect of a Compound ofFormula (I)-(VII) Against Ototoxicity

Peritonitis is currently one of the leading complications of continuousambulatory peritoneal dialysis (CAPD). Aminoglycosides and vancomycinare used in the treatment of CAPD peritonitis despite their potentialrisk for ototoxicity. The purpose of this study is to examine whetherototoxicity due to antibiotics used in the treatment of CAPD peritonitiscan be prevented by a compound of Formula (I)-(VII).

Patients: Eligible subjects will be men and women 18-65 years of age.

Inclusion Criteria

End-stage renal disease

Undergoing continuous ambulatory peritoneal dialysis as a renalreplacement therapy

Developing the first continuous ambulatory peritoneal dialysis relatedperitonitis episode

Exclusion Criteria

Being treated with aminoglycoside antibiotics and vancomycine within theprevious 3 months

Detection of mechanical occlusion of external ear

Having signs of disturbed integrity of tympanic membrane on otoscopy ortympanometry

History of a continuous ambulatory peritoneal dialysis relatedperitonitis

Study Design:

Arms Assigned Interventions Experimental: Compound of Drug: Compound ofFormula (I)-(VII) Formula (I)-(VII) Compound of Formula (I)-(VII) 600 mgCompound of Formula (I)-(VII) twice a day, one week after 600 mg twicedaily + administration of antibiotics vancomycine and/or amikacin NoIntervention: Control Drug: Compound of Formula (I)-(VII) Vancomycineand/or amikacin Compound of Formula (I)-(VII) 600 mg alone twice a day,one week after administration of antibiotics

Primary Outcome Measures

Threshold hearing levels (Time Frame: 4 weeks)

What is claimed is:
 1. A compound having the structure of Formula (Ia):

wherein: R₁ is C₆-C₁₀aryl or C₃-C₉heteroaryl, wherein C₆-C₁₀aryl andC₃-C₉heteroaryl are optionally substituted with one or more R₄; R₂ is H,C₁-C₄alkyl, or C₂-C₄alkenyl; R₃ is C₂-C₆alkyl, C₂-C₆alkenyl,C₁-C₄haloalkyl, optionally substituted C₃-C₆cycloalkyl, optionallysubstituted C₂-C₇heterocycloalkyl, optionally substituted C₆-C₁₀aryl,—OR₆, —NR₅R₆, —C(O)R₇, —CO₂R₆, —C(O)NR₅R₆, —N(R₅)C(O)R₇, —N(R₅)CO₂R₇,—NHS(O)₂R₇, —S(O)₂NR₅R₆,

or R₂ and R₃ together form an optionally substitutedC₂-C₇heterocycloalkyl ring; each R₄ is independently selected from F,Cl, Br, I, —CN, —NO₂, —CF₃, —OR₉, —OCF₃, —NR₈R₉, —C(O)R₁₀, —CO₂R₉,—C(O)NR₈R₉, —N(R₈)C(O)R₁₀, —N(R₈)CO₂R₁₀, —NHS(O)₂R₁₀, —S(O)₂NR₈R₉,C₁-C₆alkyl, C₃-C₆cycloalkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl,C₂-C₇heterocycloalkyl, C₆-C₁₀aryl, and C₃-C₉heteroaryl; R₅ is H orC₁-C₆alkyl; R₆ is H, C₁-C₆alkyl, optionally substituted C₃-C₆cycloalkyl,optionally substituted C₂-C₇heterocycloalkyl, optionally substitutedC₆-C₁₀aryl, optionally substituted C₃-C₉heteroaryl, optionallysubstituted C₁-C₆alkylC₆-C₁₀aryl, or optionally substitutedC₁-C₆alkylC₃-C₉heteroaryl; R₇ is C₁-C₆alkyl, optionally substitutedC₃-C₆cycloalkyl, optionally substituted C₂-C₇heterocycloalkyl,optionally substituted C₆-C₁₀aryl, C₃-C₉heteroaryl, optionallysubstituted C₁-C₆alkylC₆-C₁₀aryl, or optionally substitutedC₁-C₆alkylC₃-C₉heteroaryl; R₈ is H or C₁-C₆alkyl; R₉ is H, C₁-C₆alkyl,C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, C₆-C₁₀aryl, C₃-C₉heteroaryl,C₁-C₆alkylC₆-C₁₀aryl, or C₁-C₆alkylC₃-C₉heteroaryl; R₁₀ is C₁-C₆alkyl,C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, C₆-C₁₀aryl, C₃-C₉heteroaryl,C₁-C₆alkylC₆-C₁₀aryl, or C₁-C₆alkylC₃-C₉heteroaryl; R₁₁ is H,C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl,C₆-C₁₀aryl, C₃-C₉heteroaryl, C₁-C₆alkylC₃-C₆cycloalkyl,C₁-C₆alkylC₆-C₁₀aryl, or C₁-C₆alkylC₃-C₉heteroaryl; R₁₂ is H,C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl,C₆-C₁₀aryl, C₃-C₉heteroaryl, C₁-C₆alkylC₃-C₆cycloalkyl,C₁-C₆alkylC₆-C₁₀aryl, or C₁-C₆alkylC₃-C₉heteroaryl; or R₁₁ and R₁₂together with the nitrogen to which they are attached form an optionallysubstituted C₂-C₇heterocycloalkyl ring; R₁₃, R₁₄, R₁₅, and R₁₆ are eachindependently H or C₁-C₄alkyl; and n is an integer selected from 0-4; ora pharmaceutically acceptable salt, pharmaceutically acceptable solvateor hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof.
 2. The compound of claim 1wherein R₁ is C₆-C₁₀aryl.
 3. The compound of claim 2 wherein R₁ isphenyl.
 4. The compound of claim 3 wherein R₁ is substituted with one ormore R₄, wherein each R₄ is independently selected from F, Cl, Br, I,—CN, —NO₂, —CF₃, —OR₉, —OCF₃, —NR₈R₉, —C(O)R₁₀, —CO₂R₉, C₁-C₆alkyl, andC₁-C₆haloalkyl.
 5. The compound of claim 4 wherein R₁ is substitutedwith one R₄, wherein R₄ is selected from F, Cl, Br, I, —CN, —CF₃, —OR₉,—OCF₃, —C(O)R₁₀, —CO₂R₉, and C₁-C₆alkyl.
 6. The compound of claim 4wherein R₁ is 4-fluorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl,4-bromophenyl, 4-iodophenyl, 3-cyanophenyl, 4-trifluoromethylphenyl,4-trifluoromethoxyphenyl, 4-phenoxyphenyl, or 4-benzoylphenyl.
 7. Thecompound of claim 6 wherein R₁ is 4-chlorophenyl.
 8. The compound ofclaim 7 wherein R₁₁ and R₁₂ are each H.
 9. The compound of claim 8wherein R₁₃, R₁₄, R₁₅ and R₁₆ are each H.
 10. The compound of claim 9wherein R₂ is H.
 11. The compound of claim 9 wherein R₂ is methyl. 12.The compound of claim 10 wherein R₃ is C₂-C₄alkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, —OR₆, —CO₂R₆, —C(O)NR₅R₆, —N(H)C(O)R₇,—N(H)CO₂R₇,


13. The compound of claim 12 wherein R₆ is H, C₁-C₆alkyl, orC₁-C₆alkylC₆-C₁₀aryl, and R₇ is C₁-C₆alkyl, C₆-C₁₀aryl,C₁-C₆alkylC₆-C₁₀aryl, or C₁-C₆alkylC₃-C₉heteroaryl.
 14. The compound ofclaim 9 wherein R₂ and R₃ together form an optionally substitutedC₂-C₇heterocycloalkyl ring.
 15. The compound of claim 14 wherein R₂ andR₃ together form an optionally substituted oxetane, pyrrolidine,piperidine, or tetrahydropyran ring.
 16. A pharmaceutical compositioncomprising a therapeutically effective amount of a compound of claim 1,or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate or hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof, and a pharmaceuticallyacceptable excipient.
 17. The pharmaceutical composition of claim 16further comprising an aminoglycoside antibiotic.
 18. A method forpreventing, treating, and/or protecting against sensory hair cell deathin an individual comprising administering to the individual atherapeutically effective amount of a compound of claim 1 or apharmaceutically acceptable salt, pharmaceutically acceptable solvate orhydrate, pharmaceutically acceptable salt hydrate, or pharmaceuticallyacceptable prodrug thereof.
 19. The method of claim 18 wherein thesensory hair cell death is associated with exposure to an ototoxicagent.
 20. The method of claim 19 wherein the ototoxic agent is anaminoglycoside antibiotic.